• Epithelial-Mesenchymal Transition/genetics
• Humans
• Zinc Finger E-box-Binding Homeobox 1/genetics
• Zinc Finger E-box-Binding Homeobox 1/metabolism
• Female
• Methylation
• Zinc Finger E-box Binding Homeobox 2/genetics
• RNA, Ribosomal, 28S/metabolism
• RNA, Ribosomal, 28S/genetics
• Cell Line, Tumor
• RNA, Small Nucleolar/genetics
• RNA, Small Nucleolar/metabolism
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/metabolism
• Twist-Related Protein 1/genetics
• Twist-Related Protein 1/metabolism
• Gene Expression Regulation, Neoplastic
• Epigenesis, Genetic
• Nuclear Proteins

• PAIR Sein
• INCa
• SIRIC
• ANR

• cancer stem cells
• preclinical research

Triple-negative breast cancer (TNBC) lacks all of three treatment targets (estrogen receptor-α, ER-α; progesterone receptor, PgR; and human epidermal growth factor receptor 2, HER2) and is usually associated with a poor clinical outcome; however, several sex steroid receptors, such as androgen receptor (AR), ER-β, and G-protein-coupled estrogen receptor, are frequently expressed and their biological and clinical importance has been suggested. Despite the structural similarity between sex steroid hormones (androgens and estrogens) or receptors (AR and ER-β), similar signaling mechanisms of these hormones, and the coexistence of these hormones and their receptors in TNBC in a clinical setting, most studies or reviews focused on only one of these receptors, and rarely reviewed them in a comprehensive way. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on common and differing features of hormone actions.

Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually associated with a poor clinical outcome; however, hormone unresponsiveness, which is the most important biological characteristic of TNBC, only means the lack of nuclear estrogenic signaling through the classical estrogen receptor (ER), ER-α. Several sex steroid receptors other than ER-α: androgen receptor (AR), second ER, ER-β, and non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER), are frequently expressed in TNBC and their biological and clinical importance has been suggested by a large number of studies. Despite the structural similarity between each sex steroid hormone (androgens and estrogens) or each receptor (AR and ER-β), and similarity in the signaling mechanisms of these hormones, most studies or reviews focused on one of these receptors, and rarely reviewed them in a comprehensive way. Considering the coexistence of these hormones and their receptors in TNBC in a clinical setting, a comprehensive viewpoint would be important to correctly understand the association between the carcinogenic mechanism or pathobiology of TNBC and sex steroid hormones. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on the common and divergent features of the action of these hormones.

• G-protein-coupled estrogen receptor (GPER)
• androgen
• androgen receptor
• estrogen
• estrogen receptor-beta
• sex steroid hormones
• triple-negative breast cancer (TNBC)

• androgen antagonist
• androgen receptor
• triple-negative breast cancer

• J3-9272 Javna Agencija za Raziskovalno Dejavnost RS

• Breast cancer
• Targeted therapies

• R21 CA267147 NCI NIH HHS
• T32 GM007315 NIGMS NIH HHS

• Doxorubicin
• TGFβ1
• Triple-negative breast cancer
• siRNA

• Androgen Receptor
• FOXA1
• GATA3
• Prognosis
• TNBC
• qRT-PCR

• Adult
• Age of Onset
• Aged
• Feasibility Studies
• Female
• GATA3 Transcription Factor/analysis
• Hepatocyte Nuclear Factor 3-alpha/analysis
• Humans
• Immunohistochemistry
• Lymph Nodes/pathology
• Middle Aged
• Neoplasm Proteins/analysis
• Prognosis
• RNA, Messenger/analysis
• Receptors, Androgen/analysis
• Receptors, Androgen/genetics
• Retrospective Studies
• Reverse Transcriptase Polymerase Chain Reaction
• Sensitivity and Specificity
• Triple Negative Breast Neoplasms/chemistry
• Triple Negative Breast Neoplasms/mortality

Background: miRNAs (microRNAs) play a key role in triple-negative breast cancer (TNBC) progression, and its heterogeneity at the expression, pathological and clinical levels. Stratification of breast cancer subtypes on the basis of genomics and transcriptomics profiling, along with the known biomarkers’ receptor status, has revealed the existence of subgroups known to have diverse clinical outcomes. Recently, several studies have analysed expression profiles of matched mRNA and miRNA to investigate the underlying heterogeneity of TNBC and the potential role of miRNA as a biomarker within cancers. However, the miRNA-mRNA regulatory network within TNBC has yet to be understood. Results and Findings: We performed model-based integrated analysis of miRNA and mRNA expression profiles on breast cancer, primarily focusing on triple-negative, to identify subtype-specific signatures involved in oncogenic pathways and their potential role in patient survival outcome. Using univariate and multivariate Cox analysis, we identified 25 unique miRNAs associated with the prognosis of overall survival (OS) and distant metastases-free survival (DMFS) with “risky” and “protective” outcomes. The association of these prognostic miRNAs with subtype-specific mRNA genes was established to investigate their potential regulatory role in the canonical pathways using anti-correlation analysis. The analysis showed that miRNAs contribute to the positive regulation of known breast cancer driver genes as well as the activation of respective oncogenic pathway during disease formation. Further analysis on the “risk associated” miRNAs group revealed significant regulation of critical pathways such as cell growth, voltage-gated ion channel function, ion transport and cell-to-cell signalling. Conclusion: The study findings provide new insights into the potential role of miRNAs in TNBC disease progression through the activation of key oncogenic pathways. The results showed previously unreported subtype-specific prognostic miRNAs associated with clinical outcome that may be used for further clinical evaluation.

• biomarkers and signalling pathway.
• epigenetics
• genomics
• integrated analysis
• microRNA
• triple negative breast cancer

• FOXA1
• androgen receptor
• apocrine-type
• avoidance of chemotherapy
• basal-like subtype
• period-shortening of chemotherapy
• triple-negative breast cancer

• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor
• Disease Management
• Duration of Therapy
• Female
• Gene Expression
• Humans
• Immunohistochemistry
• Neoadjuvant Therapy
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Staging
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/etiology
• Triple Negative Breast Neoplasms/mortality
• Triple Negative Breast Neoplasms/pathology

Invasive mammary carcinomas that spontaneously develop in female cats are associated with high mortality, and resemble the most aggressive human breast cancers, especially triple-negative breast cancer (TNBC). Transcriptome studies showed that TNBCs are a heterogeneous group that includes a potentially hormone-dependent subtype named luminal-AR. Some authors proposed an immunohistochemical definition of the luminal-AR subtype, which is not only positive for Androgen Receptor (AR), but also either positive for the transcription factor Forkhead box A1 (FOXA1), or negative for basal markers. The objectives of this study were to describe AR and FOXA1 expressions in feline mammary carcinomas (FMCs), their prognostic value, and if their coexpression could define a “luminal-AR” subtype of triple-negative mammary carcinomas in cats.

In a previously described retrospective cohort of 180 female cats with FMCs, with a 2-year follow-up post-mastectomy, we assessed AR, FOXA1, ER, PR, Ki-67, HER2, and CK14 expressions by automated immunohistochemistry.

Of the 180 FMCs, 57 (32%) were luminal; i.e., ER and/or PR positive, and 123 (68%) were triple-negative (ER–, PR– and HER2–) FMCs. AR overexpression (found in 33 cases/180, 18%) and FOXA1 index ≥1% (64/180, 36%) were associated with a longer disease-free interval, overall survival, and cancer-specific survival in cats with FMC. Analysis of AR, FOXA1 and CK14 coexpression in triple-negative FMCs showed that AR+ triple-negative FMCs were heterogeneous: there existed an AR+ FOXA1+ CK14– subgroup (n = 7) associated with a better cancer-specific survival by multivariate survival analysis (HR = 0.26, 95% CI: 0.07–0.89, p = 0.03) compared to AR+ FOXA1–CK14+ triple-negative FMCs (n = 46) (HR = 1.00), independently of the pathologic tumor size and pathologic nodal stage. The non-basal-like subtype of triple-negative FMCs that coexpresses AR and FOXA1 (the AR+ FOXA1+ CK14– subgroup) could represent the equivalent of the luminal-AR subgroup of human triple-negative breast cancer.

We identified an AR+ FOXA1+ CK14– subgroup of triple-negative FMCs that might correspond to the luminal-AR subgroup of human triple-negative breast cancers. Cats with FMC may be interesting spontaneous animal models to investigate new strategies targeting the androgen receptor, especially in the aggressive subtype of AR+ basal-like triple-negative mammary carcinomas with loss of FOXA1 expression (the AR+ FOXA1–CK14+ subgroup).

• Androgen receptor
• FOXA1
• Feline mammary carcinoma
• Luminal-AR breast cancer
• Spontaneous animal model
• Triple-negative breast cancer

• Breast cancer
• Tumour biomarkers

• U10 CA180821 NCI NIH HHS

Heterogeneity and lack of targeted therapies represent the two main impediments to precision treatment of triple-negative breast cancer (TNBC), and therefore, molecular subtyping and identification of therapeutic pathways are required to optimize medical care. The aim of the present study was to define robust TNBC subtypes with clinical relevance.

Gene expression profiling by means of DNA chips was conducted in an internal TNBC cohort composed of 238 patients. In addition, external data (n = 257), obtained by using the same DNA chip, were used for validation. Fuzzy clustering was followed by functional annotation of the clusters. Immunohistochemistry was used to confirm transcriptomics results: CD138 and CD20 were used to test for plasma cell and B lymphocyte infiltrations, respectively; MECA79 and CD31 for tertiary lymphoid structures; and UCHL1/PGP9.5 and S100 for neurogenesis.

We identified three molecular clusters within TNBC: one molecular apocrine (C1) and two basal-like-enriched (C2 and C3). C2 presented pro-tumorigenic immune response (immune suppressive), high neurogenesis (nerve infiltration), and high biological aggressiveness. In contrast, C3 exhibited adaptive immune response associated with complete B cell differentiation that occurs in tertiary lymphoid structures, and immune checkpoint upregulation. External cohort subtyping by means of the same approach proved the robustness of these results. Furthermore, plasma cell and B lymphocyte infiltrates, tertiary lymphoid structures, and neurogenesis were validated at the protein levels by means of histological evaluation and immunohistochemistry.

Our work showed that TNBC can be subcategorized in three different subtypes characterized by marked biological features, some of which could be targeted by specific therapies.

The online version of this article (10.1186/s13058-019-1148-6) contains supplementary material, which is available to authorized users.

• Breast cancer
• Immunome
• Molecular subtypes
• Neurogenesis
• Tertiary lymphoid structures
• Transcriptomics
• Triple-negative

• Adjuvant chemotherapy
• Docetaxel
• Early breast cancer
• Ixabepilone
• Poor prognosis breast cancer
• Triple-negative breast cancer

• Logistic regression
• cellwise outliers
• gene networks
• sparsity

Triple-negative breast cancer refers to breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (Her2). This study aimed to identify the key pathways and genes and find the potential initiation and progression mechanism of triple-negative breast cancer (TNBC).

We downloaded the gene expression profiles of GSE76275 from Gene Expression Omnibus (GEO) datasets. This microarray Super-Series sets are composed of gene expression data from 265 samples which included 67 non-TNBC and 198 TNBC. Next, all the differentially expressed genes (DEGs) with p<0.01 and fold change ≥1.5 or ≤-1.5 were identified.

56 upregulated and 151 downregulated genes were listed and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis was performed. These significantly changed genes were mainly involved in the biological process termed prostate gland morphogenesis, inner ear morphogenesis, cell maturation, digestive tract morphogenesis, autonomic nervous system development, monovalent inorganic anion homeostasis, neural crest cell development, regulation of dendrite extension and glial cell proliferation, immune system process termed T cell differentiation, regulation of immune response, and macrophage activation. Genes are mainly involved in the KEGG pathway termed Oocyte meiosis. All DEGs underwent survival analysis using datasets from The Cancer Genome Atlas (TCGA) integrated by cBioPortal, of which amplification of SRY-related HMG-box 8 (SOX8), androgen receptor (AR), and Chromosome 9 Open Reading Frame 152 (C9orf152) were significantly negative while Nik Related Kinase (NRK) and RAS oncogene family 30 (RAB30) were positively correlated to the life expectancy (p<0.05).

In conclusion, these pathways and genes identified could help understanding the mechanism of development of TNBC. Besides, SOX8, AR, C9orf152, NRK and RAB30, and other key genes and pathways might be promising targets for the TNBC treatment.

• AR
• EMPD
• ER
• FOXA1
• MPD
• Paget's disease

• Aged, 80 and over
• Female
• Humans
• Male
• Biomarkers, Tumor/analysis
• Breast Neoplasms/diagnosis
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Hepatocyte Nuclear Factor 3-alpha/genetics
• Hepatocyte Nuclear Factor 3-alpha/metabolism
• Paget Disease, Extramammary/diagnosis
• Paget Disease, Extramammary/genetics
• Paget Disease, Extramammary/pathology
• Paget's Disease, Mammary/diagnosis
• Paget's Disease, Mammary/genetics
• Paget's Disease, Mammary/pathology
• Receptors, Estrogen/metabolism
• Middle Aged
• Aged

In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation.

AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed.

AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years).

AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup.

Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.

• HSD17B1
• HSD17B2
• androgens
• breast cancer
• estrogens

• androgen receptor
• breast neoplasms
• estrogen receptor
• forkhead box A1
• prognosis

• Adult
• Aged
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• DNA Copy Number Variations/genetics
• Female
• Humans
• Immunohistochemistry
• Middle Aged
• Neoplasm Metastasis
• Neoplastic Cells, Circulating/metabolism
• Neoplastic Cells, Circulating/pathology
• Prevalence
• Receptor, ErbB-2/metabolism
• Receptors, Androgen/metabolism
• Receptors, Estrogen/metabolism
• Single-Cell Analysis

• P30 CA016672 NCI NIH HHS
• The State of Texas Rare and Aggressive Breast Cancer Research Program
• Epic Sciences
• The Morgan Welch Inflammatory Breast Cancer Research Program

• BDNF
• Breast cancer
• Chinese herbal medicine
• Endothelial cell

• Brain-Derived Neurotrophic Factor/metabolism
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cyclooxygenase 2/metabolism
• Drugs, Chinese Herbal/adverse effects
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Magnoliopsida/adverse effects
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Membrane Glycoproteins/metabolism
• Neoplasm Recurrence, Local/etiology
• Phytotherapy/adverse effects
• Plants, Medicinal/adverse effects
• Protein-Tyrosine Kinases/metabolism
• Receptor, trkB
• Signal Transduction
• Up-Regulation
• cdc42 GTP-Binding Protein/metabolism
• rac GTP-Binding Proteins/metabolism

• Taipei Veterans General Hospital
• Center of Excellence for Cancer Research at Taipei Veterans General Hospital phase II
• Cheng-Hsin Yang-Ming project

• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Estrogen Receptor alpha
• Humans
• Receptors, Androgen

• AR
• ERα
• ERβ
• Epithelial Mesenchymal Transition
• GR
• MR
• Mesenchymal Epithelial Transition
• PR
• Steroid Nuclear Receptors
• breast cancer