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Ning JY, Zhang ZH, Zhang J, Liu YM, Li GC, Wang AM, Li Y, Shan X, Wang JH, Zhang X, Zhao Y. Ginsenoside Rg3 decreases breast cancer stem-like phenotypes through impairing MYC mRNA stability. Am J Cancer Res 2024; 14:601-615. [PMID: 38455405 PMCID: PMC10915333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 01/28/2024] [Indexed: 03/09/2024] Open
Abstract
Breast cancer stem cells (BCSCs) are responsible for breast cancer metastasis, recurrence and treatment resistance, all of which make BCSCs potential drivers of breast cancer aggression. Ginsenoside Rg3, a traditional Chinese herbal medicine, was reported to have multiple antitumor functions. Here, we revealed a novel effect of Rg3 on BCSCs. Rg3 inhibits breast cancer cell viability in a dose- and time-dependent manner. Importantly, Rg3 suppressed mammosphere formation, reduced the expression of stemness-related transcription factors, including c-Myc, Oct4, Sox2 and Lin28, and diminished ALDH(+) populations. Moreover, tumor-bearing mice treated with Rg3 exhibited robust delay of tumor growth and a decrease in tumor-initiating frequency. In addition, we found that Rg3 suppressed breast cancer stem-like properties mainly through inhibiting MYC expression. Mechanistically, Rg3 accelerated the degradation of MYC mRNA by enhancing the expression of the let-7 family, which was demonstrated to bind to the MYC 3' untranslated region (UTR). In conclusion, our findings reveal the remarkable suppressive effect of Rg3 on BCSCs, suggesting that Rg3 is a promising therapeutic treatment for breast cancer.
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Affiliation(s)
- Jin-Yue Ning
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical UniversityDalian 116011, Liaoning, China
| | - Zi-Han Zhang
- Medical College of Tianjin UniversityTianjin 300072, China
| | - Jia Zhang
- Department of Oncology, People’s Hospital of NingxiangNingxiang 410600, Hunan, China
| | - Yong-Min Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical UniversityDalian 116011, Liaoning, China
| | - Guan-Chu Li
- National Clinical Research Center for Gynecology and Obstetrics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and TechnologyWuhan 430000, China
| | - A-Man Wang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical UniversityDalian 116011, Liaoning, China
| | - Ying Li
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical UniversityDalian 116011, Liaoning, China
| | - Xiu Shan
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical UniversityDalian 116011, Liaoning, China
| | - Ju-Hong Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021, China
| | - Xu Zhang
- Department of Thoracic Surgery, The Second Hospital of Dalian Medical University Cardiovascular HospitalDalian 116000, Liaoning, China
| | - Yi Zhao
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian Medical UniversityDalian 116011, Liaoning, China
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Lučić I, Kurtović M, Mlinarić M, Piteša N, Čipak Gašparović A, Sabol M, Milković L. Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches. Int J Mol Sci 2023; 24:10683. [PMID: 37445860 DOI: 10.3390/ijms241310683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
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Affiliation(s)
- Ivan Lučić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Monika Mlinarić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Nikolina Piteša
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Lidija Milković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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Choupani E, Mahmoudi Gomari M, Zanganeh S, Nasseri S, Haji-Allahverdipoor K, Rostami N, Hernandez Y, Najafi S, Saraygord-Afshari N, Hosseini A. Newly Developed Targeted Therapies Against the Androgen Receptor in Triple-Negative Breast Cancer: A Review. Pharmacol Rev 2023; 75:309-327. [PMID: 36781219 DOI: 10.1124/pharmrev.122.000665] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 09/26/2022] [Accepted: 10/31/2022] [Indexed: 12/15/2022] Open
Abstract
Among different types of breast cancers (BC), triple-negative BC (TNBC) amounts to 15% to 20% of breast malignancies. Three principal characteristics of TNBC cells are (i) extreme aggressiveness, (ii) absence of hormones, and (iii) growth factor receptors. Due to the lack or poor expression of the estrogen receptor, human epidermal growth factor receptor 2, and progesterone receptor, TNBC is resistant to hormones and endocrine therapies. Consequently, chemotherapy is currently used as the primary approach against TNBC. Expression of androgen receptor (AR) in carcinoma cells has been observed in a subset of patients with TNBC; therefore, inhibiting androgen signaling pathways holds promise for TNBC targeting. The new AR inhibitors have opened up new therapy possibilities for BC patients carrying AR-positive TNBC cells. Our group provides a comprehensive review of the structure and function of the AR and clinical evidence for targeting the cell's nuclear receptor in TNBC. We updated AR agonists, inhibitors, and antagonists. We also presented a new era of genetic manipulating CRISPR/Cas9 and nanotechnology as state-of-the-art approaches against AR to promote the efficiency of targeted therapy in TNBC. SIGNIFICANCE STATEMENT: The lack of effective treatment for triple-negative breast cancer is a health challenge. The main disadvantages of existing treatments are their side effects, due to their nonspecific targeting. Molecular targeting of cellular receptors, such as androgen receptors, increased expression in malignant tissues, significantly improving the survival rate of breast cancer patients.
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Affiliation(s)
- Edris Choupani
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Mohammad Mahmoudi Gomari
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Saeed Zanganeh
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Sherko Nasseri
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Kaveh Haji-Allahverdipoor
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Neda Rostami
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Yaeren Hernandez
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Safa Najafi
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Neda Saraygord-Afshari
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
| | - Arshad Hosseini
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran (E.C., M.M.G., N.S.-A., A.H.); Cell Therapy and Regenerative Medicine Comprehensive Center, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran (S.Z.); Department of Molecular Medicine, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran (S.N., K.H.-a.); Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran (N.R.); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona (Y.H.); and Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran (S.N.)
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Ibragimova M, Tsyganov M, Litviakov N. Tumour Stem Cells in Breast Cancer. Int J Mol Sci 2022; 23:ijms23095058. [PMID: 35563449 PMCID: PMC9099719 DOI: 10.3390/ijms23095058] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/27/2022] [Accepted: 04/30/2022] [Indexed: 12/12/2022] Open
Abstract
Tumour stem cells (CSCs) are a self-renewing population that plays important roles in tumour initiation, recurrence, and metastasis. Although the medical literature is extensive, problems with CSC identification and cancer therapy remain. This review provides the main mechanisms of CSC action in breast cancer (BC): CSC markers and signalling pathways, heterogeneity, plasticity, and ecological behaviour. The dynamic heterogeneity of CSCs and the dynamic transitions of CSC− non-CSCs and their significance for metastasis are considered.
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Affiliation(s)
- Marina Ibragimova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (M.T.); (N.L.)
- Laboratory of Genetic Technologies, Siberian State Medical University, 2, Moscow Tract, 634050 Tomsk, Russia
- Biological Institute, National Research Tomsk State University, 36, Lenin, 634050 Tomsk, Russia
- Correspondence:
| | - Matvey Tsyganov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (M.T.); (N.L.)
| | - Nikolai Litviakov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 5, Kooperativny Street, 634050 Tomsk, Russia; (M.T.); (N.L.)
- Laboratory of Genetic Technologies, Siberian State Medical University, 2, Moscow Tract, 634050 Tomsk, Russia
- Biological Institute, National Research Tomsk State University, 36, Lenin, 634050 Tomsk, Russia
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Waza AA, Tarfeen N, Majid S, Hassan Y, Mir R, Rather MY, Shah NUD. Metastatic Breast Cancer, Organotropism and Therapeutics: A Review. Curr Cancer Drug Targets 2021; 21:813-828. [PMID: 34365922 DOI: 10.2174/1568009621666210806094410] [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: 04/10/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 11/22/2022]
Abstract
The final stage of breast cancer involves spreading breast cancer cells to the vital organs like the brain, liver lungs and bones in the process called metastasis. Once the target organ is overtaken by the metastatic breast cancer cells, its usual function is compromised causing organ dysfunction and death. Despite the significant research on breast cancer metastasis, it's still the main culprit of breast cancer-related deaths. Exploring the complex molecular pathways associated with the initiation and progression of breast cancer metastasis could lead to the discovery of more effective ways of treating the devastating phenomenon. The present review article highlights the recent advances to understand the complexity associated with breast cancer metastases, organotropism and therapeutic advances.
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Affiliation(s)
- Ajaz Ahmad Waza
- Multidisciplinary Research Unit (MRU), Government Medical College (GMC) Srinagar, J & K, 190010. India
| | - Najeebul Tarfeen
- Centre of Research for Development, University of Kashmir, Srinagar 190006 . India
| | - Sabhiya Majid
- Department of Biochemistry, Government Medical College (GMC) Srinagar, J & K, 190010. India
| | - Yasmeena Hassan
- Division of Nursing, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Soura, Srinagar, J & K. India
| | - Rashid Mir
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Kingdom of Saudi Arabia, Tabuk. Saudi Arabia
| | - Mohd Younis Rather
- Multidisciplinary Research Unit (MRU), Government Medical College (GMC) Srinagar, J & K, 190010. India
| | - Naseer Ue Din Shah
- Centre of Research for Development, University of Kashmir, Srinagar 190006 . India
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6
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Trailblazing perspectives on targeting breast cancer stem cells. Pharmacol Ther 2021; 223:107800. [PMID: 33421449 DOI: 10.1016/j.pharmthera.2021.107800] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
Breast cancer (BCa) is one of the most prevalent malignant tumors affecting women's health worldwide. The recurrence and metastasis of BCa have made it a long-standing challenge to achieve remission-persistent or disease-undetectable clinical outcomes. Cancer stem cells (CSCs) possess the ability to self-renew and generate heterogeneous tumor bulk. The existence of CSCs has been found to be vital in the initiation, metastasis, therapy resistance, and recurrence of tumors across cancer types. Because CSCs grow slowly in their dormant state, they are insensitive to conventional chemotherapies; however, when CSCs emerge from their dormant state and become clinically evident, they usually acquire genetic traits that make them resistant to existing therapies. Moreover, CSCs also show evidence of acquired drug resistance in synchrony with tumor relapses. The concept of CSCs provides a new treatment strategy for BCa. In this review, we highlight the recent advances in research on breast CSCs and their association with epithelial-mesenchymal transition (EMT), circulating tumor cells (CTCs), plasticity of tumor cells, tumor microenvironment (TME), T-cell modulatory protein PD-L1, and non-coding RNAs. On the basis that CSCs are associated with multiple dysregulated biological processes, we envisage that increased understanding of disease sub-classification, selected combination of conventional treatment, molecular aberration directed therapy, immunotherapy, and CSC targeting/sensitizing strategy might improve the treatment outcome of patients with advanced BCa. We also discuss novel perspectives on new drugs and therapeutics purposing the potent and selective expunging of CSCs.
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7
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Solvent fractions of selected Ethiopian medicinal plants used in traditional breast cancer treatment inhibit cancer stem cells in a breast cancer cell line. BMC Complement Med Ther 2020; 20:366. [PMID: 33238963 PMCID: PMC7687706 DOI: 10.1186/s12906-020-03154-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 11/10/2020] [Indexed: 12/26/2022] Open
Abstract
Background The incidence and mortality of breast cancer in women is increasing worldwide. Breast cancer contains a subpopulation of cells known as cancer stem cells (CSCs). The CSCs are believed to be responsible for chemotherapeutic resistance and are also involved in tumor initiation, progression, evolution, and metastasis to distant sites. The present study aimed to investigate the anti-CSC potential of selected Ethiopian medicinal plants traditionally used for breast cancer treatment. Methods The solvent fractions of three medicinal plants (the ethyl acetate fraction of Vernonia leopoldi, the aqueous fraction of Sideroxylon oxyacanthum, and the chloroform fraction of Clematis simensis) resulting from the methanolic crude extracts were selected based on their previously demonstrated cytotoxic effects on breast cancer cell lines. The effect of these solvent fractions on the status of the cancer stem cell subpopulation of the JIMT-1 cell line was assessed by flow cytometric evaluation of the proportion of aldehyde dehydrogenase positive cells and by measuring colony forming efficiency in a serum-free soft agar assay after treatment. Effects on cell migration using a wound healing assay and on tumor necrosis factor-α-induced translocation of nuclear factor-kappa B to the cell nucleus were also investigated. Results The solvent fractions showed a dose-dependent reduction in the aldehyde dehydrogenase positive subpopulation of JIMT-1 cells. The chloroform fraction of C. simensis (80 μg/mL) completely blocked colony formation of JIMT-1 cells. The wound healing assay showed that all fractions significantly reduced cell migration. The ethyl acetate fraction of V. leopoldi (0.87 μg/mL) significantly inhibited tumor necrosis factor-α-induced nuclear factor-kappa B translocation to the nucleus. Conclusion The solvent fractions of the medicinal plants showed desirable activities against breast cancer stem cells in the JIMT-1 cell line, which warrants further studies.
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Tuasha N, Petros B. Heterogeneity of Tumors in Breast Cancer: Implications and Prospects for Prognosis and Therapeutics. SCIENTIFICA 2020; 2020:4736091. [PMID: 33133722 PMCID: PMC7568790 DOI: 10.1155/2020/4736091] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/20/2020] [Accepted: 09/28/2020] [Indexed: 05/16/2023]
Abstract
Breast cancer is the most commonly diagnosed form of cancer in women comprising 16% of all female cancers. The disease shows high intertumoral and intratumoral heterogeneity posing diagnostic and therapeutic challenges with unpredictable clinical outcome and response to existing therapy. Mounting evidence is ascertaining that breast cancer stem cells (CSCs) are responsible for tumor initiation, progression, recurrence, evolution, metastasis, and drug resistance. Therapeutics selectively targeting the CSCs based on distinct surface molecular markers and enhanced intracellular activities of these cells continue to evolve and hold significant promise. Having plethora of heterogeneity accompanied with failure of existing conventional therapeutics and poor prognosis, the present review focuses on elucidating the main signaling pathways in breast CSCs as major therapeutic targets. The role of developments in nanomedicine and miRNA as targeted delivery of therapeutic anticancer agents is also highlighted.
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Affiliation(s)
- Nigatu Tuasha
- Addis Ababa University, College of Natural Science, Department of Microbial, Cellular and Molecular Biology, P.O. Box 1176, Addis Ababa, Ethiopia
| | - Beyene Petros
- Addis Ababa University, College of Natural Science, Department of Microbial, Cellular and Molecular Biology, P.O. Box 1176, Addis Ababa, Ethiopia
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9
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Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X. Breast cancer lung metastasis: Molecular biology and therapeutic implications. Cancer Biol Ther 2018; 19:858-868. [PMID: 29580128 PMCID: PMC6300341 DOI: 10.1080/15384047.2018.1456599] [Citation(s) in RCA: 194] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/18/2018] [Accepted: 03/19/2018] [Indexed: 02/05/2023] Open
Abstract
Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.
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Affiliation(s)
- Liting Jin
- Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, China
| | - Bingchen Han
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Emily Siegel
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yukun Cui
- Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Armando Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- CONTACT Xiaojiang Cui Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis Building 2065, Los Angeles, CA 90048
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10
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Ding M, Wang X. Antagonism between Hedgehog and Wnt signaling pathways regulates tumorigenicity. Oncol Lett 2017; 14:6327-6333. [PMID: 29391876 DOI: 10.3892/ol.2017.7030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 03/30/2017] [Indexed: 01/16/2023] Open
Abstract
The crosstalk of multiple cellular signaling pathways is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation and metastasis. The Hedgehog (Hh) and Wnt signaling pathways are both considered to be essential regulators of cell proliferation, differentiation and oncogenesis. Recent studies have indicated that the Hh and Wnt signaling pathways are closely associated and involved in regulating embryogenesis and cellular differentiation. Hh signaling acts upstream of the Wnt signaling pathway, and negative regulates Wnt activity via secreted frizzled-related protein 1 (SFRP1), and the Wnt/β-catenin pathway downregulates Hh activity through glioma-associated oncogene homolog 3 transcriptional regulation. This evidence suggests that the imbalance of Hh and Wnt regulation serves a crucial role in cancer-associated processes. The activation of SFRP1, which inhibits Wnt, has been demonstrated to be an important cross-point between the two signaling pathways. The present study reviews the complex interaction between the Hh and Wnt signaling pathways in embryogenesis and tumorigenicity, and the role of SFRP1 as an important mediator associated with the dysregulation of the Hh and Wnt signaling pathways.
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Affiliation(s)
- Mei Ding
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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Candelaria PV, Rampoldi A, Harbuzariu A, Gonzalez-Perez RR. Leptin signaling and cancer chemoresistance: Perspectives. World J Clin Oncol 2017; 8:106-119. [PMID: 28439492 PMCID: PMC5385432 DOI: 10.5306/wjco.v8.i2.106] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/20/2016] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.
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Xu LZ, Li SS, Zhou W, Kang ZJ, Zhang QX, Kamran M, Xu J, Liang DP, Wang CL, Hou ZJ, Wan XB, Wang HJ, Lam EWF, Zhao ZW, Liu Q. p62/SQSTM1 enhances breast cancer stem-like properties by stabilizing MYC mRNA. Oncogene 2017; 36:304-317. [PMID: 27345399 PMCID: PMC5269535 DOI: 10.1038/onc.2016.202] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 02/04/2016] [Accepted: 04/08/2016] [Indexed: 12/12/2022]
Abstract
Aberrant p62 overexpression has been implicated in breast cancer development. Here, we found that p62 expression was elevated in breast cancer stem cells (BCSCs), including CD44+CD24- fractions, mammospheres, ALDH1+ populations and side population cells. Indeed, short-hairpin RNA (shRNA)-mediated knockdown of p62 impaired breast cancer cells from self-renewing under anchorage-independent conditions, whereas ectopic overexpression of p62 enhanced the self-renewal ability of breast cancer cells in vitro. Genetic depletion of p62 robustly inhibited tumor-initiating frequencies, as well as growth rates of BCSC-derived tumor xenografts in immunodeficient mice. Consistently, immunohistochemical analysis of clinical breast tumor tissues showed that high p62 expression levels were linked to poorer clinical outcome. Further gene expression profiling analysis revealed that p62 was positively correlated with MYC expression level, which mediated the function of p62 in promoting breast cancer stem-like properties. MYC mRNA level was reduced upon p62 deletion by siRNA and increased with p62 overexpression in breast cancer cells, suggesting that p62 positively regulated MYC mRNA. Interestingly, p62 did not transactivate MYC promoter. Instead, p62 delayed the degradation of MYC mRNA by repressing the expression of let-7a and let-7b, thus promoting MYC mRNA stabilization at the post-transcriptional level. Consistently, let-7a and let-7b mimics attenuated p62-mediated MYC mRNA stabilization. Together, these findings unveiled a previously unappreciated role of p62 in the regulation of BCSCs, assigning p62 as a promising therapeutic target for breast cancer treatments.
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Affiliation(s)
- L-Z Xu
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - S-S Li
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - W Zhou
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Z-J Kang
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Q-X Zhang
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - M Kamran
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - J Xu
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - D-P Liang
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - C-L Wang
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Z-J Hou
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - X-B Wan
- Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - H-J Wang
- Department of Breast Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - E W-F Lam
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Z-W Zhao
- Department of Breast Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
- Department of Breast Surgery, The Second Affiliated Hospital, Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian, Liaoning 116000, China. E-mail:
| | - Q Liu
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, 9 Western Section, Lvshun South Street, Lvshunkou District, Dalian, Liaoning 116044, China E-mail:
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Kotiyal S, Bhattacharya S. Breast cancer stem cells, EMT and therapeutic targets. Biochem Biophys Res Commun 2014; 453:112-6. [PMID: 25261721 DOI: 10.1016/j.bbrc.2014.09.069] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Accepted: 09/17/2014] [Indexed: 12/23/2022]
Abstract
A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo "epithelial to mesenchymal transition" (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.
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Affiliation(s)
- Srishti Kotiyal
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, UttarPradesh, India
| | - Susinjan Bhattacharya
- Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, UttarPradesh, India.
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