Androgen Receptor Expression in Estrogen Receptor-Negative Breast Cancer Immunohistochemical, Clinical, and Prognostic Associations

Agoff, S. Nicholas; Swanson, Paul E.; Linden, Hannah M.; Hawes, Stephen E.; Lawton, Thomas J.

doi:10.1309/42f0-0d0d-jd0j-5edt

Cited by 126 publications

(179 citation statements)

References 13 publications

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“…AR typically is present in a greater proportion of breast tumors (80-90%) than ERa (50-80%; reviewed in refs. 5,9) and previous studies have indicated the potential for AR to predict disease progression (10,11). In addition, we have reported that the level of the AR predicts both the likelihood and the duration of response to therapy with the synthetic progestin, medroxyprogesterone acetate (12), and that disease progression after medroxyprogesterone acetate therapy is associated with inactivating mutations in the AR gene (13).…”

Section: Introductionmentioning

confidence: 59%

Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer

et al. 2009

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There is emerging evidence that the balance between estrogen receptor-A (ERA) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERA were coexpressed in the majority (80-90%) of breast tumor cells. KaplanMeier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERApositive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERA transactivation activity and 17B-estradiol-stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERA signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogenresponsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17B-estradiol on breast cancer cells. [Cancer Res 2009;69(15):6131-40]

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Section: Introductionmentioning

confidence: 59%

Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer

et al. 2009

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“…AR expression in ERa-negative breast cancer is correlated with a lower Nottingham grade and apocrine differentiation (Niemeier et al 2010). The association between AR and survival is not so clear in ERa-negative breast cancers as in ERa-positive breast cancers; studies have reported either no association (Gonzalez et al 2008, Peters et al 2009, Park et al 2011 or an association with improved survival (Agoff et al 2003, Luo et al 2010, Witzel et al 2013). In addition, one meta-analysis reported that AR is associated with improved overall survival in ERa-negative breast cancer (Qu et al 2013), while the other reported no association (Vera-Badillo et al 2014).…”

Section: Era-negative Breast Cancermentioning

confidence: 99%

“…DHT induced p53 expression in MCF7 breast cancer cells (Wang et al 2013a,b), while AR expression has been associated with a lack of p53 expression in unselected human breast cancers (Ogawa et al 2008). However, in a different cohort that was separated into ERa-positive or ERa-negative disease, no association between AR and p53 was observed in either group (Agoff et al 2003). Therefore, while there is some evidence to support the functional interactions among AR, PTEN and p53, further studies are required to clarify the role of this pathway in breast cancer cells.…”

Section: Ar Pten P53 and Pi3k/aktmentioning

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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“…However, it is currently unclear how to stratify individual breast cancers based on whether they will respond favourably to androgen treatment or not. In different breast cancer cell lines, modulation of androgen signalling can have growth-inhibitory or growth-promoting effects (Birrell et al 1995, Ortmann et al 2002, Greeve et al 2004, Lyu et al 2014, reviewed in Fioretti et al (2014), and this extends to the applicability of AR expression as a prognostic marker in specific subtypes of breast cancer (Kuenen-Boumeester et al 1996, Agoff et al 2003, Peters et al 2009, Kraus et al 2010, Gasparini et al 2014. Such conflicting reports/data raise concerns for the clinical efficacy of androgen modulation in breast cancer.…”

Section: Ar Expression In Mammary Epitheliummentioning

confidence: 99%

Bringing androgens up a NOTCH in breast cancer

Tarulli

Butler

Tilley

et al. 2014

Endocrine-Related Cancer

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While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/ recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

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Androgen Receptor Expression in Estrogen Receptor-Negative Breast Cancer Immunohistochemical, Clinical, and Prognostic Associations

Cited by 126 publications

References 13 publications

Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer

Androgen Receptor Inhibits Estrogen Receptor-α Activity and Is Prognostic in Breast Cancer

Complexities of androgen receptor signalling in breast cancer

Bringing androgens up a NOTCH in breast cancer

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