Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1)

Greeve, Melissa A.; Allan, Richard; Harvey, Jennet; Bentel, Jacqueline M.

doi:10.1677/jme.0.0320793

Cited by 71 publications

(62 citation statements)

References 58 publications

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“…This inhibitory effect was associated with an increment of a proportion of cells in G 0 /G 1 phase or increased levels of p21 and/or p27 (Lapointe & Labrie 2001, Greeve et al 2004. In our present study, E 2 -mediated proliferation of T-47D cells was significantly inhibited by DHT, which was also associated with an increment of 17bHSD2 expression level (Fig.…”

Section: K Takagi Et Al: Intratumoral Androgens In Breast Carcinomasupporting

confidence: 66%

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Takagi

Miki

Nagasaki³

et al. 2010

Endocrine-Related Cancer

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Sex steroids play important roles in the development of many human breast carcinomas, and aromatase inhibitors are used for the anti-estrogen therapy. Recent studies have demonstrated that aromatase suppressed 5a-dihydrotestosterone (DHT) synthesis in breast carcinoma cells, but intratumoral concentration of androgens and its significance have not been reported in the breast carcinoma patients treated with aromatase inhibitors. Therefore, we examined androgen concentrations in breast carcinoma tissues treated with exemestane, and further performed in vitro studies to characterize the significance of androgen actions. Intratumoral DHT concentration was significantly higher in breast carcinoma tissues following exemestane treatment (nZ9) than those without the therapy (nZ7), and 17b-hydroxysteroid dehydrogenase type 2 (17bHSD2) status was significantly altered to be positive after the treatment. Following in vitro studies showed that 17bHSD2 expression was dose dependently induced by both DHT and exemestane in T-47D breast carcinoma cells, but these inductions were not additive. DHT-mediated induction of 17bHSD2 expression was markedly suppressed by estradiol (E 2 ) in T-47D cells. E 2 -mediated cell proliferation was significantly inhibited by DHT in T-47D cells, associated with an increment of 17bHSD2 expression level. These findings suggest that intratumoral androgen actions are increased during exemestane treatment. 17bHSD2 is a potent DHT-induced gene in human breast carcinoma, and may not only be involved in anti-proliferative effects of DHT on breast carcinoma cells but also serve as a potential marker for response to aromatase inhibitor in the breast carcinoma patients.

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Section: K Takagi Et Al: Intratumoral Androgens In Breast Carcinomasupporting

confidence: 66%

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Takagi

Miki

Nagasaki³

et al. 2010

Endocrine-Related Cancer

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“…Interestingly, in the MCF-7 cell line, which is the most widely used AR þ / ER þ breast cancer cell model, different groups also reported androgens' antiproliferative (7,8,39,42,43) as well as proliferative effects (44,45). These lines of controversial evidence most likely are due to the complexity of the AR pathway and lack of acknowledgment of broad mechanisms of androgenic effects in breast cancer, in vivo and in intro.…”

Section: /Ermentioning

confidence: 99%

“…Unaromatizable androgens, such as dihydrotestosterone (DHT), inhibit tumor proliferation and induce apoptosis by activating androgen receptor (AR) in AR þ /ER þ breast cancers (7)(8)(9). Among all female breast carcinomas, 60% to 70% are AR positive.…”

Section: Introductionmentioning

confidence: 99%

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Wang

et al. 2014

Molecular Cancer Therapeutics

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NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, being tested in multiple clinical trials, including breast cancer. NVP-BEZ235 selectively induces cell growth inhibition in a subset, but not all, breast cancer cell lines. However, it remains a challenge to distinguish between sensitive and resistant tumors, particularly in the pretreatment setting. Here, we used ten breast cancer cell lines to compare NVP-BEZ235 sensitivity and in the context of androgen receptor (AR) activation during NVP-BEZ235 treatment. We also used female SCID mice bearing breast tumor xenografts to investigate the beneficial effect of dihydrotestosterone/NVP-BEZ235 combination treatment compared with each alone. We found that AR-positive breast cancer cell lines are much more sensitive to NVP-BEZ235 compared with AR-negative cells, regardless of PTEN or PI3KCA status. Reintroducing AR expression in NVP-BEZ235 nonresponsive AR-negative cells restored the response. DHT/NVP-BEZ235 combination not only resulted in a more significant growth inhibition than either drug alone, but also achieved tumor regression and complete responses for AR þ /ER þ tumors. This beneficial effect was mediated by dihydrotestosterone (DHT)-induced PTEN and KLLN expression. Furthermore, DHT could also reverse NVP-BEZ235-induced side effects such as skin rash and weight loss. Our data suggest that AR expression may be an independent predictive biomarker for response to NVP-BEZ235. AR induction could add benefit during NVP-BEZ235 treatment in patients, especially with AR þ

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“…Indeed, numerous studies in animal models have shown that androgens, at physiological concentrations, stimulate growth in mammary cancer (Smith & King 1972, Liao et al 1998, Xie et al 1999, Liao & Dickson 2002, Somboonporn & Davis 2004, while other reports have indicated that their administration results in tumour regression of chemically and hormone-induced breast cancers (Costlow et al 1976, Zhou et al 2000. The inhibitory capability of androgens in human breast cancer has been documented in experimental and clinical studies (Poulin et al 1988, Jørgensen et al 1997, Szelei et al 1997, Adams 1998, Labrie et al 2003, Greeve et al 2004, Somboonporn & Davis 2004, though the absence of anti-proliferative effects on several human breast cancer cells has also been reported (Roy et al 1992). Interestingly, several studies have shown that androgens may exhibit an initial inhibitory effect that shift to a late stimulatory effect on human breast cancer cell proliferation (Lippman et al 1976, Hackenberg et al 1993, Labrie et al 1998, Aspinall et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern

Pérez‐Palacios

Santillán

Garcı́a-Becerra

et al. 2006

Journal of Endocrinology

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Breast cancer is a sex steroid hormone-dependent malignant neoplasia. The role of oestradiol in this malignancy has been well documented; however, the involvement of androgens has remained controversial. To determine the role of nonphenolic androgen metabolites in human breast cancer, we studied the metabolism of [ C] testosterone and [14 C] androstenedione in oestrogen-dependent MCF-7 cells and non-oestrogen-dependent MDA-MB 231 cells, at different substrate concentrations (1-10 mM) and time periods (30 min-48 h). Cultured non-oestrogen-dependent HeLa and yeast cells served as controls. Metabolites were identified and quantified by reverse isotope dilution. A distinctive pattern of androgen metabolism was identified in MCF-7 cells, being the 5a-androstane-3a,17b-diol (3a,5a-diol) and its 3b epimer (3b,5a-diol), the major conversion products of testosterone (48$3%), with 5a-dihydrotestosterone as intermediary. The formation of 3a,5a-diol and 3b,5a-diol (diols) was substrate concentration-and time-dependent, and abolished by finasteride. In contrast, very little of any diol formation was observed in MDA-MB 231, HeLa and yeast cell incubations. Additional enzyme gene expression studies revealed an overexpression of 5a-steroid reductase type-1 in MCF-7 cells, as compared with MDA-MB 231 cells. The oestrogen-like activities of diols were assessed in HeLa cells co-transfected with expression vectors for a or b subtypes of the human oestrogen receptor (hER) genes and for an oestrogen-responsive reporter gene. The results show that 3b, 5a-diol and to a lesser extent 3a,5a-diol bind with high relative affinity to hERa and hERb.Both diols induced hER-mediated reporter gene transactivation in a dose-response manner, similar to that induced by oestradiol, though with lower potency, an effect that was abolished by ICI-182 780. Furthermore, 3b,5a-diol and to lesser extent 3a,5a-diol induced MCF-7 cell proliferation. The overall results demonstrated that MCF-7 cells exhibit enhanced expression and activity of androgen-metabolising enzymes, leading to rapid and large diol formation, and provide evidence that these androgen metabolites exert a potent oestrogen-agonistic effect, at genomic level, in oestrogen-dependent breast cancer cells. The data suggest that diols may act as in situ intracrine factors in breast cancer and that its formation can be pharmacologically inhibited.

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Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1)

Cited by 71 publications

References 58 publications

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment

Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern

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