Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma

Fujii, Rika; Hanamura, Toru; Suzuki, Takashi; Gohno, Tatsuyuki; Shibahara, Yukiko; Niwa, Toshimitsu; Yamaguchi, Yuri; Ohnuki, Koji; Kakugawa, Yoichiro; Higuchi, Hisashi; Ishida, Toru; Sasano, Hironobu; Ohuchi, Noriaki; Hayashi, Shin Ichi

doi:10.1016/j.jsbmb.2014.08.019

Cited by 53 publications

(56 citation statements)

References 44 publications

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“…Because preclinical studies suggest a role for AR in resistance to tamoxifen (15,61) and aromatase inhibitors (62,63), it will be important to test the prognostic power of the AR in the context of the cut-points defined herein using tissues collected from large contemporary, prospective breast cancer cohorts.…”

Section: Discussionmentioning

confidence: 99%

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

Ricciardelli

Bianco‐Miotto

Jindal

et al. 2018

Clinical Cancer Research

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Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival.Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n ¼ 219; validation cohort, n ¼ 418; 77% and 79% estrogen receptor alpha (ERa) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts.Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P ¼ 0.015) and validation (HR, 0.50; P ¼ 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERa-positive tumors and AR positivity !78% had the best survival in both cohorts (P < 0.0001). Among the combined ERa-positive cases, those with comparable or higher levels of AR (AR:ERa-positivity ratio >0.87) had the best outcomes (P < 0.0001).Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

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Section: Discussionmentioning

confidence: 99%

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

Ricciardelli

Bianco‐Miotto

Jindal

et al. 2018

Clinical Cancer Research

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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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“…Clinically, a high AR to ERα expression ratio in primary breast tumors is associated with failure of Tam treatment within 5 years and decreased disease free survival during Tam treatment [4]. Higher AR activity has also been found in tumors that recur following AI therapy [12]. …”

Section: Introductionmentioning

confidence: 99%

Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer

Ciupek

Rechoum

et al. 2015

Breast Cancer Res Treat

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Purpose Tamoxifen (Tam) resistance represents a significant clinical problem in estrogen receptor (ER) -positive breast cancer. We previously showed that decreased expression of Rho guanine nucleotide dissociation inhibitor (Rho GDI), a negative regulator of the Rho GTPase pathway, is associated with Tam resistance. We now discover that androgen receptor (AR) is overexpressed in cells with decreased Rho GDI and seek to determine AR’s contribution to resistance. Methods We engineered ER -positive cell lines with stable knock-down (KD) of Rho GDI (KD cells). Resistance mechanisms were examined using microarray profiling, protein-interaction studies, growth and reporter gene assays, and Western blot analysis combined with a specific AR antagonist and other signaling inhibitors. Results Tam-resistant tumors and cell lines with low Rho GDI levels exhibited upregulated AR expression. Microarray of Rho GDI KD cells indicated that activation of EGFR and ER was associated with Tam treatment. When AR levels were elevated interaction between AR and EGFR was detected. Constitutive and Tam-induced phosphorylation of EGFR and ERK1/2 was blocked by the AR antagonist Enzalutamide, suggesting that AR-mediated EGFR activation was a mechanism of resistance in these cells. Constitutive ERα phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR-mediated EGFR signaling activated ER. Tam exhibited agonist activity in AR over-expressing cells, stimulating ERα transcriptional activity and proliferation, which was blocked by Enzalutamide and gefitinib. Conclusions We describe a novel model of AR-mediated Tam resistance through activation of EGFR signaling leading to ER activation in ER -positive cells with low expression of Rho GDI.

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Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma

Cited by 53 publications

References 44 publications

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

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

Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer

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