Androgen receptor activation in Endocrine-Resistant ER-positive breast cancer

2019 ◽  
Author(s):  
Heloisa Helena Milioli ◽  
Kee Ming Chia ◽  
Neil Portman ◽  
Aliza Yong ◽  
Gerald Tarulli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Receptor Activation ◽  
Er Positive ◽  
Androgen Receptor Activation ◽  
Positive Breast Cancer

scholarly journals Prohibitin promotes androgen receptor activation in ER-positive breast cancer

Cell Cycle ◽  
2017 ◽  
Vol 16 (8) ◽  
pp. 776-784 ◽  
Author(s):  
Pengying Liu ◽  
Yumei Xu ◽  
Wenwen Zhang ◽  
Yan Li ◽  
Lin Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Receptor Activation ◽  
Er Positive ◽  
Androgen Receptor Activation ◽  
Positive Breast Cancer

scholarly journals Estrogen Receptor Positive Breast Cancer with High Expression of Androgen Receptor has Less Cytolytic Activity and Worse Response to Neoadjuvant Chemotherapy but Better Survival

2019 ◽  
Vol 20 (11) ◽  
pp. 2655 ◽  
Author(s):  
Maiko Okano ◽  
Masanori Oshi ◽  
Ali Linsk Butash ◽  
Mariko Asaoka ◽  
Eriko Katsuta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Tumor Infiltrating Lymphocytes ◽  
Cytolytic Activity ◽  
Er Positive ◽  
Infiltrating Lymphocytes ◽  
Response To Neoadjuvant Chemotherapy ◽  
Positive Breast Cancer

Estrogen receptor (ER) positive breast cancer (BC), the most abundant BC subtype, is notorious for poor response to neoadjuvant chemotherapy (NAC). The androgen receptor (AR) was reported to support estradiol-mediated ER activity in an in vitro system. Recently, ER-positive BC with fewer tumor infiltrating lymphocytes (TILs) was shown to have a better prognosis, opposite to the trend seen with ER-negative BC. We hypothesized that ER-positive BC with high expression of AR will have fewer TILs and an inferior response to NAC, but with a better prognosis. In both TCGA and METABRIC cohorts, AR expression was significantly higher in ER-positive BCs compared to ER-negatives (p < 0.001, p < 0.001, respectively) and it correlated with ER expression (R = 0.630, R = 0.509, respectively). In ER-positive tumors, AR high tumors enriched UV response down (NES = 2.01, p < 0.001), and AR low tumors enriched DNA repair (NES = −2.02, p < 0.001). AR high tumors were significantly associated with procancer regulatory T-cells, and AR low tumors were associated with anticancer immune cells, such as CD4, CD8, and Gamma-Delta T-cells and memory B-cells in ER-positive BC (p < 0.01). Further, cytolytic activity was significantly lower in AR high BC in both cohorts. Finally, AR high tumors had a significantly lower rate of attaining pathological complete response to NAC (GSE22358), but better survival. In conclusion, our results demonstrated that high AR has fewer tumor infiltrating lymphocytes as well as cytolytic activity and an inferior response to NAC, but better survival in ER-positive BC.

scholarly journals Androgen receptor signaling pathways as a target for breast cancer treatment

2016 ◽  
Vol 23 (10) ◽  
pp. R485-R498 ◽  
Author(s):  
Elisabetta Pietri ◽  
Vincenza Conteduca ◽  
Daniele Andreis ◽  
Ilaria Massa ◽  
Elisabetta Melegari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Triple Negative ◽  
Pubertal Development ◽  
Her2 Positive ◽  
Age Related ◽  
Clinical Scenarios ◽  
Er Positive ◽  
Positive Breast Cancer

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.

scholarly journals Androgen Receptor Expression Associates With Distinctive Clinicopathological and Molecular Features in ER-Positive and ER-Negative Breast Cancer

2021 ◽  
Author(s):  
Taobo Hu ◽  
Yiqiang Liu ◽  
Guiyang Zhao ◽  
Shu Wang ◽  
Mengping Long
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Clinicopathological Characteristics ◽  
Receptor Expression ◽  
Molecular Features ◽  
Molecular Correlation ◽  
Er Positive ◽  
Er Expression ◽  
Positive Breast Cancer

Abstract Background: Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression of breast cancer remains unclear. Methods: In this study, we analyzed the clinicopathological and molecular features associated AR loss in ER-positive and ER-negative breast cancer respectively, trying to elucidate the molecular correlation between AR and ER. Results: Our results showed that AR loss was associated with different clinicopathological characteristics in ER-positive and ER-negative breast cancer. Moreover, the expression of AR was correlated with different molecular features in ER-positive and ER-negative breast cancer.Conclusions: These results suggest that the role of AR in ER-positive breast cancer is distinctive from that in ER-negative breast cancer.

scholarly journals Androgen Receptor Expression Associates With Distinctive Clinicopathological and Molecular Features in ER-Positive and ER-Negative Breast Cancer

2021 ◽  
Author(s):  
Taobo Hu ◽  
Yiqiang Liu ◽  
Guiyang Zhao ◽  
Shu Wang ◽  
Mengping Long
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Clinicopathological Characteristics ◽  
Receptor Expression ◽  
Molecular Features ◽  
Molecular Correlation ◽  
Er Positive ◽  
Er Expression ◽  
Positive Breast Cancer

Abstract Background Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression of breast cancer remains unclear. Methods In this study, we analyzed the clinicopathological and molecular features associated AR loss in ER-positive and ER-negative breast cancer respectively, trying to elucidate the molecular correlation between AR and ER. Results Our results showed that AR loss was associated with different clinicopathological characteristics in ER-positive and ER-negative breast cancer. Moreover, the expression of AR was correlated with different molecular features in ER-positive and ER-negative breast cancer. Conclusions These results suggest that the role of AR in ER-positive breast cancer is distinctive from that in ER-negative breast cancer.

scholarly journals OR05-06 The Androgen Receptor Is a Tumour Suppressor in Estrogen Receptor Positive Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Theresa E Hickey ◽  
Luke Selth ◽  
Kee Ming Chia ◽  
Heloisa Milioli ◽  
Daniel Roden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Strategy ◽  
Tumour Suppressor ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract There is strong interest in targeting the androgen receptor (AR) in estrogen receptor (ER) positive breast cancer, but widespread confusion exits as to what therapeutic strategy - agonism or antagonism - is appropriate. Current understanding of AR predominantly stems from the field of prostate cancer, where AR is the key oncogenic driver and therapeutic target. An ensuing assumption is that AR promotes malignancy in breast cancer and should be therapeutically antagonised. However, compelling pre-clinical data to support this assumption is lacking. Since estrogen stimulates and androgen inhibits the development of normal breast tissue, we hypothesized that AR acts as a tumour suppressor in the breast and that AR agonism is the appropriate therapeutic strategy for ER-driven breast cancer. We tested this hypothesis using a large suite of cell line and patient-derived explant (PDE) and xenograft (PDX) models of breast cancer, including those that were resistant to current therapies and those harbouring genomic anomalies of ESR1 associated with treatment-resistant disease. Across the diverse models we found compelling evidence that AR agonism, but not antagonism, potently and durably inhibited tumour growth. A signature of AR activity derived from the xenograft models positively predicted disease survival in multiple large clinical cohorts of ER+ breast cancer, out-performing other breast cancer-specific prognostic signatures. We also show that an AR agonist can be combined with current ER target therapies such as Tamoxifen or a CDK4/6 inhibitor to maximize growth inhibition. Mechanistically, agonist-bound AR opposed ER signalling by repositioning ER and the co-activator p300 in the chromatin landscape, resulting in down-regulation of cell cycle genes. Introduction of an AR DNA binding mutant had no effect on ER signalling or estrogen-stimulated growth in breast cancer cells. As part of this study, we have generated consensus AR cistromes representing ER+ breast cancer cell lines and ER+ tumours that provide a new understanding of AR activity and clearly show differences to those associated with prostate cancer cell lines and tumours. In conclusion, our data provides a compelling biological rationale for AR agonism as a therapeutic strategy in multiple, clinically relevant contexts of ER-positive breast cancer. These findings should dispel widespread confusion over the role of AR in ER-driven breast cancer, an issue that currently hinders progress in leveraging modern AR-targeted therapies (e.g. selective androgen receptor modulators) that lack the undesirable side-effects of androgens for clinical benefit.

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