Revising the role of the androgen receptor in breast cancer

Fioretti, Flavia Marialucia; Sita‐Lumsden, Ailsa; Bevan, Charlotte L.; Brooke, Greg N.

doi:10.1530/jme-14-0030

Cited by 81 publications

(75 citation statements)

References 82 publications

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“…Expression of AR is associated with good prognosis in ER+ breast cancer (Hu et al 2011, Hilborn et al 2016, with anti-estrogenic and anti-proliferative effects in ER+ breast cancer being reported (Peters et al 2009. The anti-proliferative effect of AR is partly attributed to its inhibitory effect on ESR1 signaling in ER+ breast cancer cells (Peters et al 2009, Fioretti et al 2014. However, AR has also been reported to contribute to therapy resistance in ER+ breast cancer cells overexpressing AR, with increase in AR-to-ESR1 ratio associated with worse outcome for tamoxifen-treated patients (Cochrane et al 2014) and increased agonist activity of Tam in AR overexpressing cells.…”

Section: Nr Expression In Breast Cancer Subtypesmentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

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Section: Nr Expression In Breast Cancer Subtypesmentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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“…The signaling effect of AR depends on its interaction with ER signaling (Chia et al 2015) because a cross talk exists between these two receptors (Fioretti et al 2014).…”

Section: Figurementioning

confidence: 99%

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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“…AR expression in breast cancer is associated with an increase in cell proliferation through AR signalling [14]. However, the correlation between AR expression and prognosis remains unclear, because of conflicting reports regarding the influence of AR on tumor progression [7,11,15]. Henley et al suggested that the lack of AR expression may play a critical role in the transformation of high-grade ductal carcinoma in situ (HG-DCIS) to high-grade invasive ductal carcinoma (HG-IDC) [16].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer

et al. 2015

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Triple negative breast cancer (TNBC) is immunohistochemically characterised by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). TNBC is known for its poor prognosis and high recurrence probability. There is no effective targeted treatment for TNBC, but only adjuvant chemotherapies. There are two TNBC subtypes, basal-like and non-basal-like, which are defined based on positive cytokeratin (CK) 5/6 and/or epidermal growth factor receptor (EGFR) expression. In particular, CK5/6 expression is reported to correlate with TNBC recurrence. TNBC lacks ER-α expression, but some TNBCs are known to express the androgen receptor (AR). Moreover, although p53 accumulation is detected in various malignant tumors, its influence on adjuvant chemotherapy for patients with TNBC remains unclear. The aim of this study was to assess the combined immunohistochemical expression of CK 5/6, AR, and p53 as a potential prognostic marker of adjuvant chemotherapy for patients with TNBC. The expression of CK5/6, AR, and p53 in formalin-fixed and paraffin-embedded (FFPE) surgical sections from 52 patients with TNBC was analysed by immunohistochemistry (IHC) and the co-expression patterns in individual cells were investigated by immunofluorescent (IF) staining. Low AR expression was correlated with high clinical stage (P < 0.05) and low nuclear grade (P < 0.05). The expression of CK5/6 and p53 did not correlate with clinicopathological features. Patients who needed adjuvant chemotherapy presented the worst prognosis. In particular, when the IHC expression pattern was CK5/6 (-), AR (-), and p53 (+), the disease free survival (DFS) and overall survival (OS) were the worst. On the other hand, patients with AR (+) and p53 (-) TNBC presented a good prognosis. The analysis of the co-expression status of these three markers showed that no cells presented both AR and CK5/6 expression. Furthermore, TP53 mRNA expression was higher in patients with AR-negative TNBC (P < 0.05) and in patients with the worst prognosis (P < 0.05) than in the other patients. These results suggested that, in patients with CK5/6-negative TNBC, AR expression correlated with good prognosis, but p53 accumulation correlated with poor prognosis. The present IHC markers allowed us to predict the post-surgery prognosis of patients with TNBC. In conclusion, TNBCs are heterogeneous. Patients with the CK5/6 (-), AR (-), and p53 (+) TNBC subtype, evaluated by IHC, presented the worst prognosis. These IHC markers will be helpful to follow patients with TNBC.

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Revising the role of the androgen receptor in breast cancer

Cited by 81 publications

References 82 publications

Emerging functional roles of nuclear receptors in breast cancer

Emerging functional roles of nuclear receptors in breast cancer

Androgen receptor signaling pathways as a target for breast cancer treatment

Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer

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