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1
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Cheng Y, Zhang W, Sun Q, Wang X, Shang Q, Liu J, Zhang Y, Liu R, Sun C. Probing the biological efficacy and mechanistic pathways of natural compounds in breast cancer therapy via the Hedgehog signaling pathway. J Pharm Anal 2025; 15:101143. [PMID: 40291019 PMCID: PMC12023894 DOI: 10.1016/j.jpha.2024.101143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 10/25/2024] [Accepted: 11/05/2024] [Indexed: 04/30/2025] Open
Abstract
Breast cancer (BC) is one of the most prevalent malignant tumors affecting women worldwide, with its incidence rate continuously increasing. As a result, treatment strategies for this disease have received considerable attention. Research has highlighted the crucial role of the Hedgehog (Hh) signaling pathway in the initiation and progression of BC, particularly in promoting tumor growth and metastasis. Therefore, molecular targets within this pathway represent promising opportunities for the development of novel BC therapies. This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC. By conducting a comprehensive review of various natural compounds, including polyphenols, terpenes, and alkaloids, we reveal both common and unique regulatory mechanisms that influence this pathway. This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC. Furthermore, by exploring the structure-activity relationships between these compounds and their molecular targets, we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway. These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics. Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.
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Affiliation(s)
- Yining Cheng
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Wenfeng Zhang
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong, 261053, China
| | - Qi Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Xue Wang
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong, 261053, China
| | - Qihang Shang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Jingyang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, and Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
| | - Yubao Zhang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Ruijuan Liu
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong, 261000, China
| | - Changgang Sun
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong, 261053, China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong, 261000, China
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2
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Wang WD, Zeng CY, Shang Y, Ni J, Li GJ, Li LP, Xi SH, Chen SZ. Thiostrepton suppresses triple-negative breast cancer through downregulating c-FLIP/SMAD2/3 signaling pathway. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:945-954. [PMID: 38634704 DOI: 10.1080/10286020.2024.2343420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 04/10/2024] [Indexed: 04/19/2024]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis of breast cancer. Thiostrepton exerts anti-tumor activities against several cancers including TNBC. Herein we discussed the new molecular mechanisms of thiostrepton in TNBC. Thiostrepton inhibited MDA-MB-231 cell viability, accompanied by a decrease of c-FLIP and p-SMAD2/3. c-FLIP overexpression reduced the sensitivity of MDA-MB-231 cells to thiostrepton, while SMAD2/3 knockdown increased the sensitivity of MDA-MB-231 cells to thiostrepton. Moreover, c-FLIP overexpression significantly increased the expression and phosphorylation of SMAD2/3 proteins and vice versa. In conclusion, our study reveals c-FLIP/SMAD2/3 signaling pathway as a novel mechanism of antitumor activity of thiostrepton.
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Affiliation(s)
- Wen-Die Wang
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Chao-Yang Zeng
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Yue Shang
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Jun Ni
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Gao-Jie Li
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Li-Ping Li
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Shuo-Han Xi
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
| | - Shu-Zhen Chen
- Department of Cancer Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
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3
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Almilaibary A. Phyto-therapeutics as anti-cancer agents in breast cancer: Pathway targeting and mechanistic elucidation. Saudi J Biol Sci 2024; 31:103935. [PMID: 38327657 PMCID: PMC10847379 DOI: 10.1016/j.sjbs.2024.103935] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/08/2024] [Accepted: 01/19/2024] [Indexed: 02/09/2024] Open
Abstract
Cancer of the breast is the mainly prevalent class of cancer in females diagnosed over the globe. It also happens to be the 2nd most prevalent reason of cancer-related deaths among females worldwide. Some of the most common type's therapies for carcinoma of the breast involve radiation therapy, chemotherapy, and resection. Many studies are being conducted to develop new therapeutic strategies for better diagnosis of breast cancer. An enormous number of anticancer medications have been developed as a result of growing understanding of the molecular pathways behind the advancement of cancer. Over the past few decades, the general survival rate has not greatly increased due to the usage of chemically manufactured medications. Therefore, in order to increase the effectiveness of current cancer treatments, new tactics and cutting-edge chemoprevention drugs are required. Phytochemicals, which are naturally occurring molecules derived from plants, are important sources for both cancer therapy and innovative medication development. These phytochemicals frequently work by controlling molecular pathways linked to the development and spread of cancer. Increasing antioxidant status, inactivating carcinogens, preventing proliferation, causing cell cycle arrest and apoptosis, and immune system control are some of the specific ways. This primary objective of this review is to provide an overview of the active ingredients found in natural goods, including information on their pharmacologic action, molecular targets, and current state of knowledge. We have given a thorough description of a number of natural substances that specifically target the pathways linked to breast carcinoma in this study. We've conducted a great deal of study on a few natural compounds that may help us identify novel targets for the detection of breast carcinoma.
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Affiliation(s)
- Abdullah Almilaibary
- Department of Family and Community Medicine, Faculty of Medicine, Albaha University, Albaha, Saudi Arabia
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4
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Wang H, Zhang Z, Ruan S, Yan Q, Chen Y, Cui J, Wang X, Huang S, Hou B. Regulation of iron metabolism and ferroptosis in cancer stem cells. Front Oncol 2023; 13:1251561. [PMID: 37736551 PMCID: PMC10509481 DOI: 10.3389/fonc.2023.1251561] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/16/2023] [Indexed: 09/23/2023] Open
Abstract
The ability of cancer stem cells (CSCs) to self-renew, differentiate, and generate new tumors is a significant contributor to drug resistance, relapse, and metastasis. Therefore, the targeting of CSCs for treatment is particularly important. Recent studies have demonstrated that CSCs are more susceptible to ferroptosis than non-CSCs, indicating that this could be an effective strategy for treating tumors. Ferroptosis is a type of programmed cell death that results from the accumulation of lipid peroxides caused by intracellular iron-mediated processes. CSCs exhibit different molecular characteristics related to iron and lipid metabolism. This study reviews the alterations in iron metabolism, lipid peroxidation, and lipid peroxide scavenging in CSCs, their impact on ferroptosis, and the regulatory mechanisms underlying iron metabolism and ferroptosis. Potential treatment strategies and novel compounds targeting CSC by inducing ferroptosis are also discussed.
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Affiliation(s)
- Hailiang Wang
- Department of Hepatobiliary Surgery, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhongyan Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
| | - Shiye Ruan
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
| | - Qian Yan
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
| | - Yubin Chen
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
| | - Jinwei Cui
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
| | - Xinjian Wang
- Department of Hepatobiliary Surgery, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Shanzhou Huang
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
- Department of General Surgery, South China University of Technology School of Medicine, Guangzhou, China
| | - Baohua Hou
- Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of General Surgery, Heyuan People’s Hospital, Heyuan, China
- Department of General Surgery, South China University of Technology School of Medicine, Guangzhou, China
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5
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Ordaz-Ramos A, Tellez-Jimenez O, Vazquez-Santillan K. Signaling pathways governing the maintenance of breast cancer stem cells and their therapeutic implications. Front Cell Dev Biol 2023; 11:1221175. [PMID: 37492224 PMCID: PMC10363614 DOI: 10.3389/fcell.2023.1221175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 06/28/2023] [Indexed: 07/27/2023] Open
Abstract
Breast cancer stem cells (BCSCs) represent a distinct subpopulation of cells with the ability to self-renewal and differentiate into phenotypically diverse tumor cells. The involvement of CSC in treatment resistance and cancer recurrence has been well established. Numerous studies have provided compelling evidence that the self-renewal ability of cancer stem cells is tightly regulated by specific signaling pathways, which exert critical roles to maintain an undifferentiated phenotype and prevent the differentiation of CSCs. Signaling pathways such as Wnt/β-catenin, NF-κB, Notch, Hedgehog, TGF-β, and Hippo have been implicated in the promotion of self-renewal of many normal and cancer stem cells. Given the pivotal role of BCSCs in driving breast cancer aggressiveness, targeting self-renewal signaling pathways holds promise as a viable therapeutic strategy for combating this disease. In this review, we will discuss the main signaling pathways involved in the maintenance of the self-renewal ability of BCSC, while also highlighting current strategies employed to disrupt the signaling molecules associated with stemness.
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Affiliation(s)
- Alejandro Ordaz-Ramos
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, México
| | - Olivia Tellez-Jimenez
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, México
| | - Karla Vazquez-Santillan
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
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6
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Ongpipattanakul C, Desormeaux EK, DiCaprio A, van der Donk WA, Mitchell DA, Nair SK. Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides. Chem Rev 2022; 122:14722-14814. [PMID: 36049139 PMCID: PMC9897510 DOI: 10.1021/acs.chemrev.2c00210] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a natural product class that has undergone significant expansion due to the rapid growth in genome sequencing data and recognition that they are made by biosynthetic pathways that share many characteristic features. Their mode of actions cover a wide range of biological processes and include binding to membranes, receptors, enzymes, lipids, RNA, and metals as well as use as cofactors and signaling molecules. This review covers the currently known modes of action (MOA) of RiPPs. In turn, the mechanisms by which these molecules interact with their natural targets provide a rich set of molecular paradigms that can be used for the design or evolution of new or improved activities given the relative ease of engineering RiPPs. In this review, coverage is limited to RiPPs originating from bacteria.
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Affiliation(s)
- Chayanid Ongpipattanakul
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Emily K. Desormeaux
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Adam DiCaprio
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
| | - Wilfred A. van der Donk
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| | - Douglas A. Mitchell
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Department of Microbiology, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
| | - Satish K. Nair
- Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA
- Departments of Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 West Gregory Drive, Urbana, Illinois 61801, USA
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7
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Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective. Bull Cancer 2022; 109:960-971. [DOI: 10.1016/j.bulcan.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/18/2022] [Accepted: 05/03/2022] [Indexed: 11/19/2022]
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8
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Yang X, Sun Y, Liu X, Jiang Z. A risk model of 10 aging-related genes for predicting survival and immune response in triple-negative breast cancer. Cancer Med 2022; 11:3182-3193. [PMID: 35297220 PMCID: PMC9385588 DOI: 10.1002/cam4.4674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/05/2022] [Accepted: 02/08/2022] [Indexed: 11/23/2022] Open
Abstract
Accumulated studies showed that the clinical significance of aging on the development and malignancy of tumors, while the relationship between aging and the prognosis, immune response in triple‐negative breast cancer (TNBC) has not been well clarified. Here, we constructed a risk model of 10 prognostic aging‐related genes (ARGs) from METABRIC database. Then, TNBC patients were classified into high‐ and low‐risk groups, the survival diversity, immune response, genomic function, and tumor mutation burden (TMB) between different risk groups were explored in METABRIC, TCGA, and GSE58812 cohorts. Results showed that patients in the high‐risk group had poorer survival outcomes compared to their counterparts (all p < 0.05), and the nomogram we established showed reliable prediction ability for survival in TNBC patients. Besides, TNBC patients with high‐risk scores had a lower expression of immune checkpoint markers and a lower fraction of activated immune cells. Furthermore, GSEA showed that Notch signaling pathway was significantly enriched in the high‐risk group. Thus, a risk model based on the aging‐related genes was developed and validated in this study, which may serve as a potential biomarker for prognosis and personalized treatment in TNBCs.
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Affiliation(s)
- Xia Yang
- Department of pathology, Sir Run Run Shaw hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yanhua Sun
- Department of Pathology, first affiliated hospital of Shenzhen University, Shenzhen, China
| | - Xia Liu
- Department of Pathology, first affiliated hospital of Shenzhen University, Shenzhen, China
| | - Zhinong Jiang
- Department of pathology, Sir Run Run Shaw hospital of Zhejiang University School of Medicine, Hangzhou, China
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9
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Almansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci 2022; 9:836417. [PMID: 35145999 PMCID: PMC8824427 DOI: 10.3389/fmolb.2022.836417] [Citation(s) in RCA: 181] [Impact Index Per Article: 60.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a kind of breast cancer that lacks estrogen, progesterone, and human epidermal growth factor receptor 2. This cancer is responsible for more than 15-20% of all breast cancers and is of particular research interest as it is therapeutically challenging mainly because of its low response to therapeutics and highly invasive nature. The non-availability of specific treatment options for TNBC is usually managed by conventional therapy, which often leads to relapse. The focus of this review is to provide up-to-date information related to TNBC epidemiology, risk factors, metastasis, different signaling pathways, and the pathways that can be blocked, immune suppressive cells of the TNBC microenvironment, current and investigation therapies, prognosis, and the role of artificial intelligence in TNBC diagnosis. The data presented in this paper may be helpful for researchers working in the field to obtain general and particular information to advance the understanding of TNBC and provide suitable disease management in the future.
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Affiliation(s)
- Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia
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10
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Bailly C. The bacterial thiopeptide thiostrepton. An update of its mode of action, pharmacological properties and applications. Eur J Pharmacol 2022; 914:174661. [PMID: 34863996 DOI: 10.1016/j.ejphar.2021.174661] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022]
Abstract
The bacterial thiopeptide thiostrepton (TS) is used as a veterinary medicine to treat bacterial infections. TS is a protein translation inhibitor, essentially active against Gram-positive bacteria and some Gram-negative bacteria. In procaryotes, TS abrogates binding of GTPase elongation factors to the 70S ribosome, by altering the structure of rRNA-L11 protein complexes. TS exerts also antimalarial effects by disrupting protein synthesis in the apicoplast genome of Plasmodium falciparum. Interestingly, the drug targets both the infectious pathogen (bacteria or parasite) and host cell, by inducing endoplasmic reticulum stress-mediated autophagy which contributes to enhance the host cell defense. In addition, TS has been characterized as a potent chemical inhibitor of the oncogenic transcription factor FoxM1, frequently overexpressed in cancers or other diseases. The capacity of TS to crosslink FoxM1, and a few other proteins such as peroxiredoxin 3 (PRX3) and the 19S proteasome, contributes to the anticancer effects of the thiopeptide. The anticancer activities of TS evidenced using diverse tumor cell lines, in vivo models and drug combinations are reviewed here, together with the implicated targets and mechanisms. The difficulty to formulate TS is a drag on the pharmaceutical development of the natural product. However, the design of hemisynthetic analogues and the use of micellar drug delivery systems should facilitate a broader utilization of the compound in human and veterinary medicines. This review shed light on the many pharmacological properties of TS, with the objective to promote its use as a pharmacological tool and medicinal product.
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Affiliation(s)
- Christian Bailly
- OncoWitan, Scientific Consulting Office, Lille, Wasquehal, 59290, France.
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11
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Siddharth S, Parida S, Muniraj N, Hercules S, Lim D, Nagalingam A, Wang C, Gyorffy B, Daniel JM, Sharma D. Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression. eLife 2021; 10:70729. [PMID: 34889737 PMCID: PMC8664295 DOI: 10.7554/elife.70729] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 11/19/2021] [Indexed: 01/16/2023] Open
Abstract
Mortality from triple negative breast cancer (TNBC) is significantly higher in African American (AA) women compared to White American (WA) women emphasizing ethnicity as a major risk factor; however, the molecular determinants that drive aggressive progression of AA-TNBC remain elusive. Here, we demonstrate for the first time that AA-TNBC cells are inherently aggressive, exhibiting elevated growth, migration, and cancer stem-like phenotype compared to WA-TNBC cells. Meta-analysis of RNA-sequencing data of multiple AA- and WA-TNBC cell lines shows enrichment of GLI1 and Notch1 pathways in AA-TNBC cells. Enrichment of GLI1 and Notch1 pathway genes was observed in AA-TNBC. In line with this observation, analysis of TCGA dataset reveals a positive correlation between GLI1 and Notch1 in AA-TNBC and a negative correlation in WA-TNBC. Increased nuclear localization and interaction between GLI1 and Notch1 is observed in AA-TNBC cells. Of importance, inhibition of GLI1 and Notch1 synergistically improves the efficacy of chemotherapy in AA-TNBC cells. Combined treatment of AA-TNBC-derived tumors with GANT61, DAPT, and doxorubicin/carboplatin results in significant tumor regression, and tumor-dissociated cells show mitigated migration, invasion, mammosphere formation, and CD44+/CD24- population. Indeed, secondary tumors derived from triple-therapy-treated AA-TNBC tumors show diminished stem-like phenotype. Finally, we show that TNBC tumors from AA women express significantly higher level of GLI1 and Notch1 expression in comparison to TNBC tumors from WA women. This work sheds light on the racial disparity in TNBC, implicates the GLI1 and Notch1 axis as its functional mediators, and proposes a triple-combination therapy that can prove beneficial for AA-TNBC.
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Affiliation(s)
- Sumit Siddharth
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Sheetal Parida
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Nethaji Muniraj
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Shawn Hercules
- Department of Biology, MacMaster University, Hamilton, Canada
| | - David Lim
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Arumugam Nagalingam
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Chenguang Wang
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Balazs Gyorffy
- MTA TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary.,Semmelweis University, Department of Bioinformatics and 2nd Dept. of Pediatrics, Budapest, Hungary
| | - Juliet M Daniel
- Department of Biology, MacMaster University, Hamilton, Canada
| | - Dipali Sharma
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
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12
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Molecular targets and therapeutics in chemoresistance of triple-negative breast cancer. Med Oncol 2021; 39:14. [PMID: 34812991 DOI: 10.1007/s12032-021-01610-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023]
Abstract
Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer (BC), which shows immunohistochemically negative expression of hormone receptor i.e., Estrogen receptor and Progesterone receptor along with the absence of Human Epidermal Growth Factor Receptor-2 (HER2/neu). In Indian scenario the prevalence of BC is 26.3%, whereas, in West Bengal the cases are of 18.4%. But the rate of TNBC has increased up to 31% and shows 27% of total BC. Conventional chemotherapy is effective only in the initial stages but with progression of the disease the effectivity gets reduced and shown almost no effect in later or advanced stages of TNBC. Thus, TNBC patients frequently develop resistance and metastasis, due to its peculiar triple-negative nature most of the hormonal therapies also fails. Development of chemoresistance may involve various factors, such as, TNBC heterogeneity, cancer stem cells (CSCs), signaling pathway deregulation, DNA repair mechanism, hypoxia, and other molecular factors. To overcome the challenges to treat TNBC various targets and molecules have been exploited including CSCs modulator, drug efflux transporters, hypoxic factors, apoptotic proteins, and regulatory signaling pathways. Moreover, to improve the targets and efficacy of treatments researchers are emphasizing on targeted therapy for TNBC. In this review, an effort has been made to focus on phenotypic and molecular variations in TNBC along with the role of conventional as well as newly identified pathways and strategies to overcome challenge of chemoresistance.
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13
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Das A, Agarwal P, Jain GK, Aggarwal G, Lather V, Pandita D. Repurposing drugs as novel triple negative breast cancer therapeutics. Anticancer Agents Med Chem 2021; 22:515-550. [PMID: 34674627 DOI: 10.2174/1871520621666211021143255] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/23/2021] [Accepted: 06/29/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Among all the types of breast cancer (BC), triple negative breast cancer (TNBC) is the most aggressive form having high metastasis and recurrence rate with limited treatment options. Conventional treatments such as chemotherapy and radiotherapy have lots of toxic side effects and also no FDA approved therapies are available till now. Repurposing of old clinically approved drugs towards various targets of TNBC is the new approach with lesser side effects and also leads to successful inexpensive drug development with less time consuming. Medicinal plants containg various phytoconstituents (flavonoids, alkaloids, phenols, essential oils, tanins, glycosides, lactones) plays very crucial role in combating various types of diseases and used in drug development process because of having lesser side effects. OBJECTIVE The present review focuses in summarization of various categories of repurposed drugs against multitarget of TNBC and also summarizes the phytochemical categories that targets TNBC singly or in combination with synthetic old drugs. METHODS Literature information was collected from various databases such as Pubmed, Web of Science, Scopus and Medline to understand and clarify the role and mechanism of repurposed synthetic drugs and phytoconstituents aginst TNBC by using keywords like "breast cancer", "repurposed drugs", "TNBC" and "phytoconstituents". RESULTS Various repurposed drugs and phytochemicals targeting different signaling pathways that exerts their cytotoxic activities on TNBC cells ultimately leads to apoptosis of cells and also lowers the recurrence rate and stops the metastasis process. CONCLUSION Inhibitory effects seen in different levels, which provides information and evidences to researchers towards drug developments process and thus further more investigations and researches need to be taken to get the better therapeutic treatment options against TNBC.
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Affiliation(s)
- Amiya Das
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, 201313. India
| | - Pallavi Agarwal
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, 201313. India
| | - Gaurav Kumar Jain
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, Govt. of NCT of Delhi, New Delhi, 110017. India
| | - Geeta Aggarwal
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, Govt. of NCT of Delhi, New Delhi, 110017. India
| | - Viney Lather
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Sector-125, Noida, 201313. India
| | - Deepti Pandita
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences & Research, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, Govt. of NCT of Delhi, New Delhi, 110017. India
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14
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Hansen MB, Postol M, Tvingsholm S, Nielsen IØ, Dietrich TN, Puustinen P, Maeda K, Dinant C, Strauss R, Egan D, Jäättelä M, Kallunki T. Identification of lysosome-targeting drugs with anti-inflammatory activity as potential invasion inhibitors of treatment resistant HER2 positive cancers. Cell Oncol (Dordr) 2021; 44:805-820. [PMID: 33939112 PMCID: PMC8090911 DOI: 10.1007/s13402-021-00603-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2021] [Indexed: 10/26/2022] Open
Abstract
PURPOSE Most HER2 positive invasive cancers are either intrinsic non-responsive or develop resistance when treated with 1st line HER2 targeting drugs. Both 1st and 2nd line treatments of HER2 positive cancers are aimed at targeting the HER2 receptor directly, thereby strongly limiting the treatment options of HER2/ErbB2 inhibition resistant invasive cancers. METHODS We used phenotypic high throughput microscopy screening to identify efficient inhibitors of ErbB2-induced invasion using 1st line HER2 inhibitor trastuzumab- and pertuzumab-resistant, p95-ErbB2 expressing breast cancer cells in conjunction with the Prestwick Chemical Library®. The screening entailed a drug's ability to inhibit ErbB2-induced, invasion-promoting positioning of lysosomes at the cellular periphery, a phenotype that defines their invasiveness. In addition, we used high throughput microscopy and biochemical assays to assess the effects of the drugs on lysosomal membrane permeabilization (LMP) and autophagy, two features connected to cancer treatment. Using 2nd line HER2 inhibitor lapatinib resistant 3-dimensional model systems, we assessed the effects of the drugs on ErbB2 positive breast cancer spheroids and developed a high-throughput invasion assay for HER2 positive ovarian cancer organoids for further evaluation. RESULTS We identified Auranofin, Colchicine, Monensin, Niclosamide, Podophyllotoxin, Quinacrine and Thiostrepton as efficient inhibitors of invasive growth of 2nd line HER2 inhibitor lapatinib resistant breast cancer spheroids and ovarian cancer organoids. We classified these drugs into four groups based on their ability to target lysosomes by inducing autophagy and/or LMP, i.e., drugs inducing early LMP, early autophagy with late LMP, late LMP, or neither. CONCLUSIONS Our results indicate that targetable lysosome-engaging cellular pathways downstream of ErbB2 contribute to invasion. They support lysosomal trafficking as an attractive target for therapy aiming at preventing the spreading of cancer cells. Since these drugs additionally possess anti-inflammatory activities, they could serve as multipurpose drugs simultaneously targeting infection/inflammation and cancer spreading.
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Affiliation(s)
- Malene Bredahl Hansen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Maria Postol
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Siri Tvingsholm
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Inger Ødum Nielsen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Tiina Naumanen Dietrich
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Pietri Puustinen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Kenji Maeda
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Christoffel Dinant
- Genome Integrity Group, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
- Core Facility for Bioimaging, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Robert Strauss
- Genome Integrity Group, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - David Egan
- Department of Cell Biology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
- Core Life Analytics, Padualaan, 83584 CH, Utrecht, The Netherlands
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Tuula Kallunki
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
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15
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Shapira S, Kazanov D, Mdah F, Yaakobi H, Herishanu Y, Perry C, Avivi I, Itchaki G, Shacham-Abulafia A, Raanani P, Hay-Levy M, Aiger G, Mashiah J, Lev-Ari S, Arber N. Feasibly of CD24/CD11b as a Screening Test for Hematological Malignancies. J Pers Med 2021; 11:724. [PMID: 34442367 PMCID: PMC8399145 DOI: 10.3390/jpm11080724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 11/17/2022] Open
Abstract
An estimated 1.24 million blood cancer cases occur annually worldwide, accounting for approximately 6% of all cancer cases. Currently, there are no standardized hematology cancer screening tests that are recommended for the general population. CD24 is a mucin-like cell surface molecule and P-selectin ligand, which plays a significant role in the maturation of B-lymphocytes and was found to be overexpressed in a number of hematological malignancies. Our primary aim was to assess the sensitivity and specificity of the CD24/CD11b-based blood test for the detection of hematological malignancies. Our cohort included 488 subjects with positive hematological cancer diagnosis (n = 122) and healthy subjects (n = 366). CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results demonstrated that the average levels of CD24/CD11b in healthy patients (21.7 ± 9.0) were statistically significantly lower compared to levels of CD24/CD11b in cancer patients (29.5 ± 18.7, p < 0.001). The highest levels of CD24/CD11b were found in multiple myeloma (39.1 ± 23.6), followed by chronic myeloid leukemia (33.0 ± 13.7) and non-Hodgkin lymphoma (32.3 ± 13.3). The test had an overall sensitivity for hematologic cancers of 78.5% (95% CI, 70.7-86.3%) and specificity of 80.2% (95% CI, 76.1-84.3%). In conclusion, our findings indicate the feasibility of a CD24/CD11b-based blood test as a screening test of hematological malignancies.
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Affiliation(s)
- Shiran Shapira
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
| | - Dina Kazanov
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
| | - Fatin Mdah
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
| | - Hadas Yaakobi
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
| | - Yair Herishanu
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
- Tel Aviv Medical Center, Department of Hematology, Tel Aviv 6423906, Israel
| | - Chava Perry
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
- Tel Aviv Medical Center, Department of Hematology, Tel Aviv 6423906, Israel
| | - Irit Avivi
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
- Tel Aviv Medical Center, Department of Hematology, Tel Aviv 6423906, Israel
| | - Gilad Itchaki
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
- Davidoff Cancer Center, Rabin Medical Center, Institute of Hematology, Petah Tikva 49100, Israel
| | - Adi Shacham-Abulafia
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
- Davidoff Cancer Center, Rabin Medical Center, Institute of Hematology, Petah Tikva 49100, Israel
| | - Pia Raanani
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
- Davidoff Cancer Center, Rabin Medical Center, Institute of Hematology, Petah Tikva 49100, Israel
| | - Mori Hay-Levy
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
| | - Gal Aiger
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
| | - Jacob Mashiah
- Tel Aviv Medical Center, The Pediatric Dermatology Unit, Tel Aviv 6423906, Israel;
| | - Shahar Lev-Ari
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
| | - Nadir Arber
- Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (S.S.); (D.K.); (F.M.); (H.Y.); (M.H.-L.); (G.A.); (S.L.-A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6423906, Israel; (Y.H.); (C.P.); (I.A.); (G.I.); (A.S.-A.); (P.R.)
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Sun X, Luo Z, Gong L, Tan X, Chen J, Liang X, Cai M. Identification of significant genes and therapeutic agents for breast cancer by integrated genomics. Bioengineered 2021; 12:2140-2154. [PMID: 34151730 PMCID: PMC8806825 DOI: 10.1080/21655979.2021.1931642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Breast cancer is the most commonly diagnosed malignancy in women; thus, more cancer prevention research is urgently needed. The aim of this study was to predict potential therapeutic agents for breast cancer and determine their molecular mechanisms using integrated bioinformatics. Summary data from a large genome-wide association study of breast cancer was derived from the UK Biobank. The gene expression profile of breast cancer was from the Oncomine database. We performed a network-wide association study and gene set enrichment analysis to identify the significant genes in breast cancer. Then, we performed Gene Ontology analysis using the STRING database and conducted Kyoto Encyclopedia of Genes and Genomes pathway analysis using Cytoscape software. We verified our results using the Gene Expression Profile Interactive Analysis, PROgeneV2, and Human Protein Atlas databases. Connectivity map analysis was used to identify small-molecule compounds that are potential therapeutic agents for breast cancer. We identified 10 significant genes in breast cancer based on the gene expression profile and genome-wide association study. A total of 65 small-molecule compounds were found to be potential therapeutic agents for breast cancer.
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Affiliation(s)
- Xiao Sun
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Zhenzhen Luo
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Liuyun Gong
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Xinyue Tan
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Jie Chen
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Xin Liang
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
| | - Mengjiao Cai
- Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shanxi P.R. China
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17
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García-Martínez A, Pérez-Balaguer A, Ortiz-Martínez F, Pomares-Navarro E, Sanmartín E, García-Escolano M, Montoyo-Pujol YG, Castellón-Molla E, Peiró G. Hedgehog gene expression patterns among intrinsic subtypes of breast cancer: Prognostic relevance. Pathol Res Pract 2021; 223:153478. [PMID: 34022683 DOI: 10.1016/j.prp.2021.153478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Hedgehog (Hh) signaling is a crucial developmental regulatory pathway recognized as a primary oncogenesis driver in various human cancers. However, its role in breast carcinoma (BC) has been underexplored. METHODS We analyzed the expression of several Hh associated genes in a clinical series and breast cancer cell lines. We included 193 BC stratified according to intrinsic immunophenotypes. Gene expression profiling ofBOC, PTCH, SMO, GLI1, GLI2, and GLI3 was performed by qRT-PCR. Results were correlated with clinical-pathological variables and outcome. RESULTS We observed expression ofGLI2 in triple-negative/basal-like (TN/BL) and GLI3 in luminal cells. In samples, BOC, GLI1, GLI2, and GLI3 expression correlated significantly with luminal tumors and good prognostic factors. In contrast, PTCH and SMO correlated with TN/BL phenotype and nodal involvement. Patients whose tumors expressed SMO had a poorer outcome, especially those with HER2 phenotype. Positive lymph-node status and high SMO remained independent poor prognostic factors. CONCLUSION Our results support a differential Hh pathway activation in BC phenotypes.SMO levels stratified patients at risk of recurrence and death in HER2 phenotype, and it showed an independent prognostic value. Therefore, SMO could be a potential therapeutic target for a subset of BC patients.
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Affiliation(s)
- Araceli García-Martínez
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain.
| | - Ariadna Pérez-Balaguer
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Fernando Ortiz-Martínez
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Eloy Pomares-Navarro
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Sanmartín
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Marta García-Escolano
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Yoel G Montoyo-Pujol
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Elena Castellón-Molla
- Pathology Dept., University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
| | - Gloria Peiró
- Research Unit, University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain; Pathology Dept., University General Hospital of Alicante, and Alicante Institute for Health and Biomedical Research (ISABIAL), Pintor Baeza 12, 03010 Alicante, Spain
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18
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Zhang R, Tu J, Liu S. Novel molecular regulators of breast cancer stem cell plasticity and heterogeneity. Semin Cancer Biol 2021; 82:11-25. [PMID: 33737107 DOI: 10.1016/j.semcancer.2021.03.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/19/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022]
Abstract
Tumors consist of heterogeneous cell populations, and tumor heterogeneity plays key roles in regulating tumorigenesis, metastasis, recurrence and resistance to anti-tumor therapies. More and more studies suggest that cancer stem cells (CSCs) promote tumorigenesis, metastasis, recurrence and drug resistance as well as are the major source for heterogeneity of cancer cells. CD24-CD44+ and ALDH+ are the most common markers for breast cancer stem cells (BCSCs). Previous studies showed that different BCSC markers label different BCSC populations, indicating the heterogeneity of BCSCs. Therefore, defining the regulation mechanisms of heterogeneous BCSCs is essential for precisely targeting BCSCs and treating breast cancer. In this review, we summarized the novel regulators existed in BCSCs and their niches for BCSC heterogeneity which has been discovered in recent years, and discussed their regulation mechanisms and the latest corresponding cancer treatments, which will extend our understanding on BCSC heterogeneity and plasticity, and provide better prognosis prediction and more efficient novel therapeutic strategies for breast cancer.
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Affiliation(s)
- Rui Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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19
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Vinogradov AA, Suga H. Introduction to Thiopeptides: Biological Activity, Biosynthesis, and Strategies for Functional Reprogramming. Cell Chem Biol 2020; 27:1032-1051. [PMID: 32698017 DOI: 10.1016/j.chembiol.2020.07.003] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/21/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022]
Abstract
Thiopeptides (also known as thiazolyl peptides) are structurally complex natural products with rich biological activities. Known for over 70 years for potent killing of Gram-positive bacteria, thiopeptides are experiencing a resurgence of interest in the last decade, primarily brought about by the genomic revolution of the 21st century. Every area of thiopeptide research-from elucidating their biological function and biosynthesis to expanding their structural diversity through genome mining-has made great strides in recent years. These advances lay the foundation for and inspire novel strategies for thiopeptide engineering. Accordingly, a number of diverse approaches are being actively pursued in the hope of developing the next generation of natural-product-inspired therapeutics. Here, we review the contemporary understanding of thiopeptide biological activities, biosynthetic pathways, and approaches to structural and functional reprogramming, with a special focus on the latter.
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Affiliation(s)
- Alexander A Vinogradov
- Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
| | - Hiroaki Suga
- Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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20
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Characteristic molecular signature of pericardial effusion identifies malignant cancer in pericardial disorder patients. Mol Cell Toxicol 2020. [DOI: 10.1007/s13273-020-00076-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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21
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Kong D, Hughes CJ, Ford HL. Cellular Plasticity in Breast Cancer Progression and Therapy. Front Mol Biosci 2020; 7:72. [PMID: 32391382 PMCID: PMC7194153 DOI: 10.3389/fmolb.2020.00072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
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Affiliation(s)
- Deguang Kong
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Connor J. Hughes
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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22
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Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17062078. [PMID: 32245065 PMCID: PMC7143295 DOI: 10.3390/ijerph17062078] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/14/2022]
Abstract
Triple-negative breast cancer (TNBC) cells are deficient in estrogen, progesterone and ERBB2 receptor expression, presenting a particularly challenging therapeutic target due to their highly invasive nature and relatively low response to therapeutics. There is an absence of specific treatment strategies for this tumor subgroup, and hence TNBC is managed with conventional therapeutics, often leading to systemic relapse. In terms of histology and transcription profile these cancers have similarities to BRCA-1-linked breast cancers, and it is hypothesized that BRCA1 pathway is non-functional in this type of breast cancer. In this review article, we discuss the different receptors expressed by TNBC as well as the diversity of different signaling pathways targeted by TNBC therapeutics, for example, Notch, Hedgehog, Wnt/b-Catenin as well as TGF-beta signaling pathways. Additionally, many epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP) and mammalian target of rapamycin (mTOR) inhibitors effectively inhibit the TNBCs, but they face challenges of either resistance to drugs or relapse. The resistance of TNBC to conventional therapeutic agents has helped in the advancement of advanced TNBC therapeutic approaches including hyperthermia, photodynamic therapy, as well as nanomedicine-based targeted therapeutics of drugs, miRNA, siRNA, and aptamers, which will also be discussed. Artificial intelligence is another tool that is presented to enhance the diagnosis of TNBC.
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Kim TH, Hanh BTB, Kim G, Lee DG, Park JW, Lee SE, Kim JS, Kim BS, Ryoo S, Jo EK, Jang J. Thiostrepton: A Novel Therapeutic Drug Candidate for Mycobacterium abscessus Infection. Molecules 2019; 24:molecules24244511. [PMID: 31835481 PMCID: PMC6943738 DOI: 10.3390/molecules24244511] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/06/2019] [Accepted: 12/06/2019] [Indexed: 02/03/2023] Open
Abstract
Mycobacterium abscessus is a rapid-growing, multidrug-resistant, non-tuberculous mycobacterial species responsible for a variety of human infections, such as cutaneous and pulmonary infections. M. abscessus infections are very difficult to eradicate due to the natural and acquired multidrug resistance profiles of M. abscessus. Thus, there is an urgent need for the development of effective drugs or regimens against M. abscessus infections. Here, we report the activity of a US Food and Drug Administration approved drug, thiostrepton, against M. abscessus. We found that thiostrepton significantly inhibited the growth of M. abscessus wild-type strains, subspecies, clinical isolates, and drug-resistant mutants in vitro and in macrophages. In addition, treatment of macrophages with thiostrepton significantly decreased proinflammatory cytokine production in a dose-dependent manner, suggesting an inhibitory effect of thiostrepton on inflammation induced during M. abscessus infection. We further showed that thiostrepton exhibits antimicrobial effects in vivo using a zebrafish model of M. abscessus infection.
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Affiliation(s)
- Tae Ho Kim
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Division of Applied Life Science (BK21plus Program), Gyeongsang National University, Jinju 52828, Korea
| | - Bui Thi Bich Hanh
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Division of Applied Life Science (BK21plus Program), Gyeongsang National University, Jinju 52828, Korea
| | - Guehye Kim
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Division of Applied Life Science (BK21plus Program), Gyeongsang National University, Jinju 52828, Korea
| | - Da-Gyum Lee
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Clinical Research Centre, Masan National Tuberculosis Hospital, Changwon 51755, Korea
| | - June-Woo Park
- Future Environmental Research Center, Korea Institute of Toxicology, Jinju 52834, Korea
- Human and Environmental Toxicology Program, Korea University of Science and Technology (UST), Daejeon 34113, Korea
| | - So Eui Lee
- Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Korea (E.-K.J.)
- Infection Control Convergence Research Center, Chungnam National University, Daejeon 35015, Korea
| | - Jae-Sung Kim
- Department of Bionano Technology, Hanyang University, Seoul 04763, Korea
| | - Byoung Soo Kim
- Department of Radiopharmaceutical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea
| | - Sungweon Ryoo
- Clinical Research Centre, Masan National Tuberculosis Hospital, Changwon 51755, Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 35015, Korea (E.-K.J.)
- Infection Control Convergence Research Center, Chungnam National University, Daejeon 35015, Korea
| | - Jichan Jang
- Molecular Mechanisms of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea
- Division of Applied Life Science (BK21plus Program), Gyeongsang National University, Jinju 52828, Korea
- Correspondence: ; Tel.: +82-553-772-1368
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Bhateja P, Cherian M, Majumder S, Ramaswamy B. The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer? Cancers (Basel) 2019; 11:cancers11081126. [PMID: 31394751 PMCID: PMC6721501 DOI: 10.3390/cancers11081126] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/23/2019] [Accepted: 07/30/2019] [Indexed: 12/24/2022] Open
Abstract
The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents.
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Affiliation(s)
- Priyanka Bhateja
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Mathew Cherian
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Sarmila Majumder
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Bhuvaneswari Ramaswamy
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
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Yang N, Wang C, Wang J, Wang Z, Huang D, Yan M, Kamran M, Liu Q, Xu B. Aurora kinase A stabilizes FOXM1 to enhance paclitaxel resistance in triple-negative breast cancer. J Cell Mol Med 2019; 23:6442-6453. [PMID: 31359594 PMCID: PMC6714217 DOI: 10.1111/jcmm.14538] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/21/2019] [Accepted: 06/03/2019] [Indexed: 12/14/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has a relatively poor outcome. Acquired chemoresistance is a major clinical challenge for TNBC patients. Previously, we reported that kinase-dead Aurora kinase A (Aurora-A) could effectively transactivate the FOXM1 promoter. Here, we demonstrate an additional pathway through which Aurora-A stabilizes FOXM1 by attenuating its ubiquitin in TNBC. Specifically, Aurora-A stabilizes FOXM1 in late M phase and early G1 phase of the cell cycle, which promotes proliferation of TNBC cells. Knock-down of Aurora-A significantly suppresses cell proliferation in TNBC cell lines and can be rescued by FOXM1 overexpression. We observe that paclitaxel-resistant TNBC cells exhibit high expression of Aurora-A and FOXM1. Overexpression of Aurora-A offers TNBC cells an additional growth advantage and protection against paclitaxel. Moreover, Aurora-A and FOXM1 could be simultaneously targeted by thiostrepton. Combination of thiostrepton and paclitaxel treatment reverses paclitaxel resistance and significantly inhibits cell proliferation. In conclusion, our study reveals additional mechanism through which Aurora-A regulates FOXM1 and provides a new therapeutic strategy to treat paclitaxel-resistant triple-negative breast cancer.
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Affiliation(s)
- Na Yang
- Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Chang Wang
- Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jian Wang
- Department of Pathology, GanZhou Municipal People's Hospital, NanChang University, GanZhou, China
| | - Zifeng Wang
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Di Huang
- Department of Breast Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Min Yan
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Muhammad Kamran
- State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Quentin Liu
- Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.,State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - BangLao Xu
- Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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Liu Y, Kim HG, Dong E, Dong C, Huang M, Liu Y, Liangpunsakul S, Dong XC. Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2685-2693. [PMID: 31351129 DOI: 10.1016/j.bbadis.2019.07.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 07/15/2019] [Accepted: 07/23/2019] [Indexed: 01/01/2023]
Abstract
Sestrin 3 (Sesn3) belongs to a small protein family that has been implicated in multiple biological processes including anti-oxidative stress, anti-aging, cell signaling, and metabolic homeostasis. However, the role of Sesn3 in hepatocellular carcinoma (HCC) remains unclear. Here we generated a Sesn3 knockout mouse model and induced HCC development by a combination of a single dose of diethylnitrosamine and chronic feeding of a choline deficient-high fat diet. After 6 months of the dietary treatment, Sesn3 knockout mice developed more severe HCC with higher levels of alpha-fetoprotein, arginase 1, and cytokeratin 19, but also higher metastatic rates than wild-type mice. Histological analysis revealed elevated extracellular matrix and cancer stem cell markers including Acta2, Cd44, and Cd133. Signaling analysis showed activated IL6-Stat3 and Akt pathways. Biochemical and microscopic analyses uncovered a novel inhibitory regulation of Gli2, a downstream transcription factor of the hedgehog signaling, by Sesn3. Two of the Gli2-regulated genes - Pdgfrb and Cd44 were upregulated in the Sesn3-deficient liver tissue. In conclusion, our data suggest that Sesn3 plays a critical tumor suppressor role in the liver partly through the inhibition of the hedgehog signaling.
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Affiliation(s)
- Yunjian Liu
- Department of Hepatobiliary Surgery, the Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi Province 332000, China; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | - Chuanpeng Dong
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yunlong Liu
- Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Suthat Liangpunsakul
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiaocheng Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
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Polonio-Alcalá E, Rabionet M, Ruiz-Martínez S, Ciurana J, Puig T. Three-Dimensional Manufactured Supports for Breast Cancer Stem Cell Population Characterization. Curr Drug Targets 2019; 20:839-851. [DOI: 10.2174/1389450120666181122113300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/03/2018] [Accepted: 11/07/2018] [Indexed: 12/23/2022]
Abstract
Breast Cancer (BC) is the most common cancer among women and the second cause of female death for cancer. When the tumor is not correctly eradicated, there is a high relapse risk and incidence of metastasis. Breast Cancer Stem Cells (BCSCs) are responsible for initiating tumors and are resistant to current anticancer therapies being in part responsible for tumor relapse and metastasis. The study of BCSCs is limited due to their low percentage within both tumors and established cell models. Hence, three-dimensional (3D) supports are presented as an interesting tool to keep the stem-like features in 3D cell culture. In this review, several 3D culture systems are discussed. Moreover, scaffolds are presented as a tool to enrich in BCSCs in order to find new specific therapeutic strategies against this malignant subpopulation. Anticancer treatments focused on BCSCs could be useful for BC patients, with particular interest in those that progress to current therapies.
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Affiliation(s)
- Emma Polonio-Alcalá
- New Therapeutic Targets Laboratory (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain
| | - Marc Rabionet
- New Therapeutic Targets Laboratory (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain
| | - Santiago Ruiz-Martínez
- New Therapeutic Targets Laboratory (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain
| | - Joaquim Ciurana
- Product, Process and Production Engineering Research Group (GREP), Department of Mechanical Engineering and Industrial Construction, University of Girona, Girona, Spain
| | - Teresa Puig
- New Therapeutic Targets Laboratory (TargetsLab), Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain
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Li J, Rong MH, Dang YW, He RQ, Lin P, Yang H, Li XJ, Xiong DD, Zhang LJ, Qin H, Feng CX, Chen XY, Zhong JC, Ma J, Chen G. Differentially expressed gene profile and relevant pathways of the traditional Chinese medicine cinobufotalin on MCF‑7 breast cancer cells. Mol Med Rep 2019; 19:4256-4270. [PMID: 30896874 PMCID: PMC6471831 DOI: 10.3892/mmr.2019.10062] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 01/01/2019] [Indexed: 02/07/2023] Open
Abstract
Cinobufotalin is a chemical compound extracted from the skin of dried bufo toads that may have curative potential for certain malignancies through different mechanisms; however, these mechanisms remain unexplored in breast cancer. The aim of the present study was to investigate the antitumor mechanism of cinobufotalin in breast cancer by using microarray data and in silico analysis. The microarray data set GSE85871, in which cinobufotalin exerted influences on the MCF‑7 breast cancer cells, was acquired from the Gene Expression Omnibus database, and the differentially expressed genes (DEGs) were analyzed. Subsequently, protein interaction analysis was conducted, which clarified the clinical significance of core genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to analyze cinobufotalin‑related pathways. The Connectivity Map (CMAP) database was used to select existing compounds that exhibited curative properties similar to those of cinobufotalin. A total of 1,237 DEGs were identified from breast cancer cells that were treated with cinobufotalin. Two core genes, SRC proto‑oncogene non‑receptor tyrosine kinase and cyclin‑dependent kinase inhibitor 2A, were identified as serving a vital role in the onset and development of breast cancer, and their expression levels were markedly reduced following cinobufotalin treatment as detected by the microarray of GSE85871. It also was revealed that the 'neuroactive ligand‑receptor interaction' and 'calcium signaling' pathways may be crucial for cinobufotalin to perform its functions in breast cancer. Conducting a matching search in CMAP, miconazole and cinobufotalin were indicated to possessed similar molecular mechanisms. In conclusion, cinobufotalin may serve as an effective compound for the treatment of a subtype of breast cancer that is triple positive for the presence of estrogen, progesterone and human epidermal growth factor receptor‑2 receptors, and its mechanism may be related to different pathways. In addition, cinobufotalin is likely to exert its antitumor influences in a similar way as miconazole in MCF‑7 cells.
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Affiliation(s)
- Jie Li
- Department of Spleen and Stomach Diseases, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region 530023, P.R. China
| | - Min-Hua Rong
- Research Department, The Affiliated Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yi-Wu Dang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Rong-Quan He
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Peng Lin
- Ultrasonics Division of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong Yang
- Ultrasonics Division of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiao-Jiao Li
- PET‑CT, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Dan-Dan Xiong
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Li-Jie Zhang
- Ultrasonics Division of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hui Qin
- Ultrasonics Division of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Cai-Xia Feng
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiao-Yi Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jin-Cai Zhong
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jie Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Toledo-Guzmán ME, Bigoni-Ordóñez GD, Ibáñez Hernández M, Ortiz-Sánchez E. Cancer stem cell impact on clinical oncology. World J Stem Cells 2018; 10:183-195. [PMID: 30613312 PMCID: PMC6306557 DOI: 10.4252/wjsc.v10.i12.183] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/15/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo- and radio-resistance. Several mechanisms have been studied to explain chemo- and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells (CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.
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Affiliation(s)
- Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico
| | | | - Miguel Ibáñez Hernández
- Departamento de Bioquímica, Laboratorio de Terapia Génica, Escuela Nacional de Ciencias Biológicas, Posgrado de Biomedicina y Biotecnología Molecular, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Mexico City 14080, Mexico.
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Tan Y, Wang Q, Xie Y, Qiao X, Zhang S, Wang Y, Yang Y, Zhang B. Identification of FOXM1 as a specific marker for triple‑negative breast cancer. Int J Oncol 2018; 54:87-97. [PMID: 30365046 PMCID: PMC6254995 DOI: 10.3892/ijo.2018.4598] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 08/30/2018] [Indexed: 12/19/2022] Open
Abstract
The present study aimed to identify the therapeutic role of the forkhead box M1 (FOXM1)-associated pathway in triple-negative breast cancer (TNBC). Using a Cancer Landscapes-based analysis, a gene regulatory network model was constructed. The present results demonstrated that FOXM1 occupies a key position in gene networks and is a critical regulatory gene in breast cancer. Using breast carcinoma gene expression data from The Cancer Genome Atlas, it was identified that FOXM1 expression was increased in the basal-like breast cancer subtype compared with other breast cancer subtypes. RNA-sequencing analysis of MDA-MB-231 cells treated with 4 and 10 µl/ml Thiostrepton identified 662 and 5,888 significantly differentially expressed genes, respectively. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that FOXM1 was highly associated with multiple biological processes and was markedly associated with metabolic pathways in TNBC. The use of Search Tool for the Retrieval of Interacting Genes/Proteins provided a critical assessment and integration of protein-protein interactions, and demonstrated the multiple important functions of FOXM1 in TNBC. Real-time cell analysis, reverse transcription-quantitative polymerase chain reaction and immunofluorescence staining were used to assess the anti-tumor activity of Thiostrepton in TNBC cells in vitro. The present results identified that suppression of FOXM1 using Thiostrepton inhibited MDA-MB-231 cell proliferation and the expression of cell cycle-associated genes, including cyclin A2, cyclin B2, checkpoint kinase 1, centrosomal protein 55 and polo like kinase 1. Immunofluorescence staining analysis demonstrated that vimentin, filamentous actin and zinc finger E-box-binding homeobox 1 were all decreased following treatment with Thiostrepton. Furthermore, a BALB/C nude mouse subcutaneous xenograft model was used to verify the function of FOXM1 in vivo. The present results demonstrated that FOXM1 inhibition significantly suppressed MDA-MB-231 cell tumorigenesis in vivo. Overall, the present results suggested that FOXM1 is a key gene that serves important roles in multiple biological processes in TNBC and that it may serve as a novel therapeutic target in TNBC.
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Affiliation(s)
- Yanli Tan
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Qixue Wang
- Department of Neurosurgery, Tianjin Neurological Institute, Tianjin 300052, P.R. China
| | - Yingbin Xie
- Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Xiaoxia Qiao
- Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Shun Zhang
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Yanan Wang
- Department of Pathology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, P.R. China
| | - Yongbin Yang
- Department of Pathology, Hebei University Medical College, Baoding, Hebei 071000, P.R. China
| | - Bo Zhang
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
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Rodrigues MFSD, Miguita L, De Andrade NP, Heguedusch D, Rodini CO, Moyses RA, Toporcov TN, Gama RR, Tajara EE, Nunes FD. GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma. Int J Oncol 2018; 53:2458-2472. [PMID: 30272273 PMCID: PMC6203148 DOI: 10.3892/ijo.2018.4572] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 06/29/2018] [Indexed: 12/24/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.
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Affiliation(s)
| | - Lucyene Miguita
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
| | - Nathália Paiva De Andrade
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
| | - Daniele Heguedusch
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
| | | | - Raquel Ajub Moyses
- Department of Head and Neck Surgery, School of Medicine, University of São Paulo, São Paulo 03178200, Brazil
| | | | - Ricardo Ribeiro Gama
- Department of Head and Neck Surgery, Barretos Cancer Hospital, Barretos 014784400, Brazil
| | - Eloiza Elena Tajara
- Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto 15090000, Brazil
| | - Fabio Daumas Nunes
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
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Chalakur-Ramireddy NKR, Pakala SB. Combined drug therapeutic strategies for the effective treatment of Triple Negative Breast Cancer. Biosci Rep 2018; 38:BSR20171357. [PMID: 29298879 PMCID: PMC5789156 DOI: 10.1042/bsr20171357] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/12/2017] [Accepted: 01/01/2018] [Indexed: 12/19/2022] Open
Abstract
TNBC (Triple Negative Breast Cancer) is a subtype of breast cancer with an aggressive phenotype which shows high metastatic capability and poor prognosis. Owing to its intrinsic properties like heterogeneity, lack of hormonal receptors and aggressive phenotype leave chemotherapy as a mainstay for the treatment of TNBC. Various studies have demonstrated that chemotherapy alone or therapeutic drugs targeting TNBC pathways, epigenetic mechanisms and immunotherapy alone have not shown significant improvement in TNBC patients. On the other hand, a combination of therapeutic drugs or addition of chemotherapy with therapeutic drugs has shown substantial improvement in results and proven to be an effective strategy for TNBC treatment. This review sheds light on effective combinational drug strategies and current clinical trial status of various combinatorial drugs for the treatment of TNBC.
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Affiliation(s)
| | - Suresh B Pakala
- Biology Division, Indian Institute of Science Education and Research (IISER) Tirupati, Andhra Pradesh, India
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Sha S, Yuan D, Liu Y, Han B, Zhong N. Targeting long non-coding RNA DANCR inhibits triple negative breast cancer progression. Biol Open 2017; 6:1310-1316. [PMID: 28760736 PMCID: PMC5612229 DOI: 10.1242/bio.023135] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Triple negative breast cancer (TNBC) is non-responsive to conventional anti-hormonal and Her2-targeted therapies, making it necessary to identify new molecular targets for therapy. Long non-coding RNA anti-differentiation ncRNA (lncRNA DANCR) was identified participating in carcinogenesis of hepatocellular carcinoma, but its expression and potential role in TNBC progression is still unclear. In the present study, our results showed that DANCR expression was increased in TNBC tissues compared with the adjacent normal tissues using quantitative real-time PCR (qRT-PCR) in 63 TNBC specimens. Patients with higher DANCR expression correlated with worse TNM stages as well as a shorter overall survival (OS) using Kaplan–Meier analysis. When the endogenous DANCR was knocked-down via specific siRNA, cell proliferation and invasion were decreased obviously in the MDA-MB-231 cells. In vivo xenograft experiments showed that knockdown of the DANCR in MDA-MB-231 cells reduced the tumor growth significantly. Furthermore, a compendium of TNBC cancer stem cell markers such as CD44, ABCG2 transporter and aldehyde dehydrogenase (ALDH1) were greatly downregulated in the MDA-MB-231 cells with DANCR knockdown. Molecular mechanistic studies revealed that knockdown of DANCR was associated with increased binding of EZH2 on the promoters of CD44 and ABCG2, and concomitant reduction of expression of these genes suggested that they may be DANCR targets in TNBC. Thus, our study demonstrated that targeting DANCR expression might be a viable therapeutic approach to treat triple negative breast cancer. Summary: Targeting LncRNA DANCR obstructs triple negative breast cancer progression by down-regulating cancer stem cell marker CD44 and ABCG2.
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Affiliation(s)
- Sha Sha
- Department of Medical Genetics, Peking University Health Science Center, Beijing, 100038 China.,Department of Medical Science, Xizang Minzu University, Xianyang, Shaanxi Province, 712082 China
| | - Dongya Yuan
- Department of Immunology and Microbiology, Xizang Minzu University, Xianyang, Shaanxi Province, 712082 China
| | - Yuejun Liu
- Department of General Surgery, Haifushan Hospital, Weifang, Shandong, 262605 China
| | - Baosan Han
- Department of General Surgery, Shanghai Jiaotong University Xinhua Hospital, Shanghai, 200240 China
| | - Nanbert Zhong
- Department of Medical Genetics, Peking University Health Science Center, Beijing, 100038 China
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HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance. Cancers (Basel) 2017; 9:cancers9050040. [PMID: 28445439 PMCID: PMC5447950 DOI: 10.3390/cancers9050040] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/10/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022] Open
Abstract
HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.
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Jafari SM, Joshaghani HR, Panjehpour M, Aghaei M, Zargar Balajam N. Apoptosis and cell cycle regulatory effects of adenosine by modulation of GLI-1 and ERK1/2 pathways in CD44 + and CD24 - breast cancer stem cells. Cell Prolif 2017; 50. [PMID: 28370734 DOI: 10.1111/cpr.12345] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 02/07/2017] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Breast cancer stem cells (CSCs) are a small population of tumour cells with the ability of self-renewal and resistance to chemotherapy. Targeting CSCs is a promising strategy for treatment of cancer. A recent study demonstrated that adenosine receptor agonists inhibit glioblastoma CSCs proliferation. At present, the effect of adenosine on breast CSCs has not been reported. Therefore, this study was designed to evaluate the effect of adenosine and its signalling pathways in breast CSCs. MATERIALS AND METHODS Anti-proliferative effect of adenosine on breast CSCs was evaluated by mammosphere formation and MTS assay. The effect of adenosine on cell cycle progression was examined using flow cytometry. Detection of apoptosis was conducted by Annexin V-FITC. The expression levels of cell cycle and apoptosis regulatory proteins as well as ERK1/2, and GLI-1 were measured by Western blot. RESULTS Adenosine reduced CSCs population and mammosphere formation in breast CSCs. Adenosine induced G1 cell cycle arrest in breast CSCs in conjunction with a marked down-regulation of cyclin D1 and CDK4. Adenosine also induced apoptosis by regulation of Bax/Bcl-2 ratio, mitochondrial membrane potential depletion and activation of caspase-6. Moreover, adenosine inhibited ERK1/2 phosphorylation and GLI-1 protein expression. CONCLUSIONS These findings indicated that adenosine induces cell cycle arrest and apoptosis through inhibition of GLI-1 and ERK1/2 pathways in breast CSCs.
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Affiliation(s)
- S M Jafari
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - H R Joshaghani
- Medical Laboratory Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - M Panjehpour
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.,Bioinformatics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - M Aghaei
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.,Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - N Zargar Balajam
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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