Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism

Hanamura, Toru; Niwa, Toshimitsu; Nishikawa, Sayo; Konno, Hirotaka; Gohno, Tatsuyuki; Tazawa, Chika; Kobayashi, Yasuhito; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Ito, Ken; Hayashi, Shin Ichi

doi:10.1007/s10549-013-2595-x

Cited by 36 publications

(25 citation statements)

References 34 publications

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“…On the other hand, in normal breast tissue, androgen production is principally mediated by 2 enzymes, 17βHSD5 and 5αR1, whose combined action generates T and DHT, as well as the cognate receptor of these steroids, the AR . in vitro and in vivo studies have suggested that androgens may also exert an anti‐proliferative and apoptotic effects .…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo effect of flutamide on steroid hormone secretion in canine and human inflammatory breast cancer cell lines

Cáceres

Monsalve

Peña

et al. 2017

Vet Comparative Oncology

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The aim was to study the effects of flutamide on cell proliferation, in vivo tumour growth and steroid production in canine and human IBC cell lines. IPC-366 and SUM149 cell cultures were exposed to flutamide concentrations for 72 hours. Additionally, IPC-366 and SUM149 xenotransplanted mice were treated subcutaneously with flutamide 3 times a week for 2 weeks. Steroid hormones determination in culture media, serum and tumour homogenates (pregnenolone, progesterone, androstenedione, testosterone, dihydrotestosterone, 17β-oestradiol and oestrone sulphate) were assayed by EIA. in vitro cell proliferation percentages showed a decrease in all flutamide dosages in IPC-366 and SUM149. in vivo flutamide reduced tumour size by 55% to 65%, and metastasis rates decreased. In treated groups, androgen levels in culture media, serum and tumour homogenates were increased as oestrogen levels decreased. These results suggest that flutamide treatment inhibits cell proliferation and promotes tumour reduction by increasing androgen levels and also support future therapy approaches.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo effect of flutamide on steroid hormone secretion in canine and human inflammatory breast cancer cell lines

Cáceres

Monsalve

Peña

et al. 2017

Vet Comparative Oncology

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“…We have established several AI-resistant cell lines that depend on an ER-mediated pathway from MCF-7 cells [36,37]. Moreover, there have been many reports that the LTED (long-term estradiol deprivation) cells overexpressed ER [5,6].…”

Section: Discussionmentioning

confidence: 99%

“…We are currently establishing several breast carcinoma cell lines to use as AI-resistance models under estrogen-depleted and androgen-supplemented conditions. Androgen metabolite-dependent and estrogen-depletion-resistant cells derived from the MCF-7 cells were recently reported to show dose-dependent activation of ER functions by the estrogenic androgen 5a-androstane-3b,17b-diol (3b-diol) and markedly decreased AR expression [36]. In addition, several ER-independent proliferative pathways have been reported as AI-resistance mechanisms, including up-regulation of the ER-mediated pathway [5,6], the growth factor receptor-mediated pathways [7,8], mitogen-activated protein kinase (MAPK), and phosphatidylinositide 3-kinase (PI3K)/Akt [6,9,37].…”

Section: Discussionmentioning

confidence: 99%

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

Fujii

Hanamura

Suzuki

et al. 2014

The Journal of Steroid Biochemistry and Molecular Biology

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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: 94%

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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Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism

Cited by 36 publications

References 34 publications

In vitro and in vivo effect of flutamide on steroid hormone secretion in canine and human inflammatory breast cancer cell lines

In vitro and in vivo effect of flutamide on steroid hormone secretion in canine and human inflammatory breast cancer cell lines

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

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

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