Androgen Receptor Expression Predicts Decreased Survival in Early Stage Triple-Negative Breast Cancer

Choi, Jung Eun; Kang, Su Hwan; Lee, Soo Jung; Bae, Young Kyung

doi:10.1245/s10434-014-3984-z

Cited by 122 publications

(102 citation statements)

References 31 publications

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“…In recent years, AR is receiving increased attention as a therapeutic target in AR-positive breast cancers, as various clinical studies have focused on the functional role of AR in breast cancer. AR is currently being tested in TNBC, in which AR is regarded to be associated with worse clinical outcome in TNBCs [38]. Safety and efficacy of AR antagonist bicalutamide, enzalutamide and abiraterone acetase have been analyzed in recent clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Zhu

Song

et al. 2016

Cell Physiol Biochem

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Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Zhu

Song

et al. 2016

Cell Physiol Biochem

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“…Conversely, some studies did not report a better outcome (Park et al 2011) or observed an even poorer prognosis (Choi et al 2015) in AR-positive/ER-negative BC. Although these controversial results are probably partly related to the use of different antibodies with variable affinities against AR and different scoring systems and cutoff values for the estimation of AR expression, the prognostic role of AR may, in actual fact, change in different BC subtypes.…”

Section: :10mentioning

confidence: 95%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

Endocrine-Related Cancer

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The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/ AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

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“…The reported rate of AR positivity in TNBC is between 0% and 53%, likely reflecting differences in the methodologies used to assess AR 29. The precise significance of AR expression in TNBC is not yet fully understood with some studies reporting adverse clinical outcomes30 and others reporting improved clinical outcomes 31. Ni et al 32 showed that androgen stimulated the HER2 signalling pathway in ER negative HER2 positive breast cancer and AR blockade in these tumours impaired cell growth.…”

Section: Therapeutic Considerationsmentioning

confidence: 99%

Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast

D’Arcy

Quinn

2018

J Clin Pathol

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Pure apocrine carcinoma of the breast is rare and has been defined by using a combination of morphologic (apocrine morphology in >90% of tumour cells) and immunohistochemical criteria (oestrogen receptor (ER) and progesterone receptor (PR) negative and androgen receptor (AR) positive). Recent advances in the molecular classification of breast tumours have uncovered a subset of breast tumours associated with high expression of androgen receptor mRNA including the so-called ‘luminal androgen receptor (LAR) tumours’ and ‘molecular apocrine tumours’ (MATs). Recognition of these tumour subsets has opened potential avenues for therapies exploiting the AR pathway in triple negative breast carcinoma (TNBC). In this second part of our two-part review, we focus on the definition of pure apocrine carcinoma, recent advances in understanding the molecular apocrine signature in breast carcinoma, its relationship to pure apocrine carcinoma defined at the level of light microscopy and immunohistochemistry (IHC) and the therapeutic implications of androgen expression in TNBC. We complete the article with a summary of the utility of IHC in stratifying apocrine lesions of the breast.

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Androgen Receptor Expression Predicts Decreased Survival in Early Stage Triple-Negative Breast Cancer

Abstract: AR-expressing TNBCs represent a distinct breast cancer subgroup with adverse clinical outcome and AR blockade could be a potential endocrine therapy for these TNBC patients. Evaluation of AR status may provide additional information on prognosis and treatment in patients with TNBC.

Cited by 122 publications

References 31 publications

Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Androgen receptor signaling pathways as a target for breast cancer treatment

Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast

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