AR collaborates with ERα in aromatase inhibitor-resistant breast cancer

Rechoum, Yassine; Rovito, Daniela; Iacopetta, Domenico; Barone, Ines; Andò, Sebastiano; Weigel, Nancy L.; O’Malley, Bert W.; Brown, Powel H.; Fuqua, Suzanne A.W.

doi:10.1007/s10549-014-3082-8

Cited by 104 publications

(109 citation statements)

References 45 publications

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“…Because AI blocks the conversion of androgens to estrogens, the levels of intratumoral androgens are elevated after treatment with AIs (34), which might up-regulate SGK3 and thus promote AI resistance. Recent studies have shown that AR expression and activity are increased in AIresistant breast cancer cells, and AR collaborates with ERα to promote AI resistance (35)(36)(37), which is in favor of our thoughts.…”

Section: Sgk3 Retains Erα Expression By Protecting Against Enr Stress-mentioning

confidence: 95%

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Wang

Zhou

Phung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum-and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.SGK3 | aromatase inhibitor | endoplasmic reticulum stress | estrogen receptor | SERCA2

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Section: Sgk3 Retains Erα Expression By Protecting Against Enr Stress-mentioning

confidence: 95%

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Wang

Zhou

Phung

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Anastrozole did not directly interact with ERα. Perhaps the expression of this receptor could be modulated by other molecules, such as insulin like growth factor (IGF-1) and fibroblast growth factor (FGF) [23], In breast cancer, the ERα did not change by anastrozole [24]. Thus, this is the first study showing an increase in ERα expression in a GBM model.…”

Section: Discussionmentioning

confidence: 87%

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

García¹,

Ramirez²,

Jiménez³

et al. 2017

J Cancer Sci Ther

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Objective: Glioblastoma multiforme is the most aggressive form of primary brain tumors, characterized by a high molecular heterogeneity hinder its treatment. Glioblastoma multiforme cells synthesize steroids through the enzyme aromatase and express estrogen receptors. Anastrozole, a specific aromatase inhibitor, plays an important role in endocrine therapy for breast cancer treatment. However, it is unknown whether this inhibitor is useful for treating glioblastoma multiforme. The aim of this work was evaluated the anastrozole effects in the viability and proliferation of malignant cells C6 in vitro as well as apoptosis, cell division, aromatase and estrogen receptor alpha expression in a GBM model in vivo.Methods: C6 cells viability under anastrozole treatment (25, 50, 75 µg/ml) was measured by MTT method and their proliferation was determinate by immunohitofluorescence. In the tumor tissue, the proliferation was evaluated using ki-67 antibody by immunohistofluorescence. ER alpha, aromatase, caspase 8 and 9 protein expression was analyzed using western-blotting. Furthermore, GPR-30, SOX2, CD133 and GFAP were evaluated by immunohistofluorescence.Results: Anastrozole produced a reduction in the viability and proliferation of the C6 cells in culture when was used at 50 μg/ml. It reduces the number of Ki67 immunofluorescent cells in approximately 50%. The aromatase expression decreased in 95%. The estrogen receptor alpha expression increased by a 20% approximately. Caspase 8 expression increased in the treated tumor tissue, although it was undetectable in the not treated group. Caspase 9 increased in approximately 95% in the treated group. All data expressed in these experimental quantifications have a statistically significant difference (p<0.05). G protein coupled receptor-30 was observed in the tumor specimens exhibiting an expression reduction in the anastrozole treated group. Conclusion:The present study demonstrates that anastrozole reduces viability and proliferation in vitro, induces apoptosis and reduces proliferation and aromatase expression in the glioblastoma Xenograft mouse model.

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“…Treatment with the antiandrogen bicalutamide restored Tam-sensitivity, alluding to the underlying interaction between AR and ERα signaling as a key mechanism regulating the response to Tam (39). Of note, aromatase overexpression, leading to increased androgen conversion to estrogens, also restored tamsensitivity (40).…”

Section: Ar Signaling In Anti-estrogen-resistant Breast Cancermentioning

confidence: 90%

“…Results from engineered estrogen-responsive MCF-7 cells overexpressing both AR and aromatase showed resistance to the inhibitory effect of anastrazol in contrast to the non-AR overexpressing cells (40). Anastrozole was unable to fully inhibit ERα signaling in AR-overexpressing cells, a notice that might be of clinical importance since tamoxifen-and/or AIresistant BrCa cells endogenously overexpress AR (40).…”

Section: Ar Signaling In Anti-estrogen-resistant Breast Cancermentioning

confidence: 96%

The Role of the Androgen Receptor Signaling in Breast Malignancies

Christopoulos

Vlachogiannis

Vogkou

et al. 2017

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Abstract. Breast cancer (BrCa) is the most common malignancy among women worldwide, and one of the leading causes of cancer-related deaths in females. Despite the development of novel therapeutic modalities, triple-negative breast cancer (TNBC) remains an incurable disease. Androgen receptor (AR) is widely expressed inBreast cancer (BrCa) is the most common solid tumor among women with an annual incidence of 123 new cases/100,000 females according to the United States Cancer Statistics and 252.710 estimated new cases in the U.S. in 2017. Despite significant progress made in therapeutics during the last 2 decades, BrCa still has a poor prognosis with 5-year survival rates of metastatic disease reaching to 26% only. BrCa is the second leading cause of death among female cancers with 40,610 estimated deaths in the U.S. expected in 2017 (1).Breast cancer comprises a heterogeneous group of diseases with variable course and outcome. Currently, BrCa is subclassified into distinct molecular subtypes named: normal breast like, luminal A/B, HER-2 related, basal-like and claudinlow (2, 3). Estrogen receptor (ER), progesterone receptor (PR) and HER2 have long been established as useful prognostic and predictive biomarkers. Hormonal therapy in ER and PR positive tumors (4), as well as the use of monoclonal antibodies in HER2 over-expressing tumors (5) have shown promising results, however overall survival of metastatic disease remains relatively low (1). To date, androgen receptor (AR) has been suggested to play a key role in breast cancer biology in certain disease subgroups (6, 7).AR is expressed in all stages of breast cancer (in-situ, primary and metastatic disease) and its contribution to the progression of disease may differ depending on the stage (8). Overall, AR expression among patients with breast cancer has been estimated at approximately 77% and varies significantly among molecular subtypes of BrCa (9). Human observational studies have associated AR with better outcome in ER + tumors, but this positive effect may be lost in ER-tumors (10, 11). Of interest, AR expression correlates with better clinicopathological features in the most aggressive form of BrCa, triple-negative breast cancer (TNBC) (12). AR seems to have distinct roles in disease development and progression depending on the tumor's hormonal environment and specifically upon relative levels of androgens and estrogens.The historically used androgens together with antiandrogens, Selective AR Modulators (SARMs) and Androgen Receptor antagonists constitute valuable options for the treatment of specific disease subpopulations. In the past decade, a wealth body of studies have focused on AR targeting along with hampering major signaling pathways 6533 This Αrticle is freely accessible online.

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AR collaborates with ERα in aromatase inhibitor-resistant breast cancer

Cited by 104 publications

References 45 publications

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Anastrozole Reduce Cell Proliferation and Induce Apoptosis in Glioblastoma Multiforme Xenograft Mouse Model

The Role of the Androgen Receptor Signaling in Breast Malignancies

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