Breast cancer: from estrogen to androgen receptor

Andò, Sebastiano; Amicis, Francesca De; Rago, Vittoria; Carpino, Amalia; Maggiolini, Marcello; Panno, Maria Luisa; Lanzino, Marilena

doi:10.1016/s0303-7207(02)00105-3

Cited by 121 publications

(91 citation statements)

References 22 publications

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“…Various in vitro studies have shown that DHT inhibits the cell proliferation of breast carcinoma cells (de Launoit et al 1991, Lapointe & Labrie 2001, Ando et al 2002 and the proapoptotic effect of DHT was also reported in breast carcinoma cells (Kandouz et al 1999). DHT treatment resulted in a rapid fall in tumor volume of ZR75-1 cells injected into athymic mice .…”

Section: Discussionmentioning

confidence: 93%

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Shibuya¹,

Suzuki²,

Miki³

et al. 2008

Endocrine Related Cancer

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It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5a-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17b-hydroxysteroid dehydrogenase type 1 (17bHSD1)), and androgen-producing enzymes (17bHSD5 and 5a-reductase type 1 (5aRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5aRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.

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Section: Discussionmentioning

confidence: 93%

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Shibuya¹,

Suzuki²,

Miki³

et al. 2008

Endocrine Related Cancer

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“…In contrast to the stimulatory effects on ER(K), PR(K), AR(C) MDA-MB-453 cells, androgen signaling has a predominantly growth inhibitory effect on ER(C), PR(C), AR(C) breast cancer cell lines (Poulin et al 1988, Birrell et al 1995, Ando et al 2002, Ortmann et al 2002, Cops et al 2008. Those findings are consistent with the clinical utility of androgenic agents as breast cancer therapies before the advent of tamoxifen (Fels 1944, The Cooperative Breast Cancer Group 1961, the favorable prognosis associated with AR expression in ER(C) breast cancers (Gonzalez-Angulo et al 2009, Castellano et al 2010, and the ability of AR to inhibit ER activity ).…”

Section: Discussionmentioning

confidence: 97%

An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity

Moore¹,

Buchanan²,

Harris³

et al. 2012

Endocrine-Related Cancer

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Recent evidence indicates that the estrogen receptor-α-negative, androgen receptor (AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype; its proliferation is stimulated by androgens such as 5α-dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that theARgene in MDA-MB-453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype.

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“…In particular, ligand-activated AR, or overexpression of constitutively active AR, has been shown to inhibit ERa activity in ZR-75-1, T-47D and MCF7 breast cancer cell lines (Lapointe et al 1999, Panet-Raymond et al 2000, Ando et al 2002, Peters et al 2009, Need et al 2012. This inhibitory effect of AR on ERa activity requires the DNA-binding domain of the AR, and in part appears to involve competition with ERa for binding to regulatory regions of ERa target genes ( Fig.…”

Section: Ar and Eramentioning

confidence: 99%

Complexities of androgen receptor signalling in breast cancer

McNamara¹,

Moore²,

Hickey³

et al. 2014

Endocrine-Related Cancer

123

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While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.

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Breast cancer: from estrogen to androgen receptor

Cited by 121 publications

References 22 publications

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity

Complexities of androgen receptor signalling in breast cancer

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