Lack of expression of androgen receptor may play a critical role in transformation from in situ to invasive basal subtype of high-grade ductal carcinoma of the breast

Hanley, Krisztina; Wang, Jianmin; Bourne, Patricia A.; Yang, Qi; Gao, Allen C.; Lyman, Gary H.; Tang, Ping

doi:10.1016/j.humpath.2007.07.007

Cited by 59 publications

(49 citation statements)

References 31 publications

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“…A well prognosis indicates that the patients survived without tumor and a worse prognosis indicates that the patients with cancer recurrence and/or who did not survive. TP53 mRNA expression levels tended to be higher in patients who had the worse prognosis than in patients who had a well prognosis (P = 0.05) 16.0 % of the cases presented EGFR (HER1) gene amplification and these were EGFR positive, but negative for CK5/6 expression [31]. Patients with CK5/6-negative but EGFR-positive TNBC may have to be classified as an independent subtype to consider the indication for EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…However, the correlation between AR expression and prognosis remains unclear, because of conflicting reports regarding the influence of AR on tumor progression [7,11,15]. Henley et al suggested that the lack of AR expression may play a critical role in the transformation of high-grade ductal carcinoma in situ (HG-DCIS) to high-grade invasive ductal carcinoma (HG-IDC) [16]. Moreover, androgen exerts a predominant inhibitory effect on the growth of breast cancer cells, both in vitro and in vivo, potentially through the induction of apoptosis [17].…”

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer

et al. 2015

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Triple negative breast cancer (TNBC) is immunohistochemically characterised by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). TNBC is known for its poor prognosis and high recurrence probability. There is no effective targeted treatment for TNBC, but only adjuvant chemotherapies. There are two TNBC subtypes, basal-like and non-basal-like, which are defined based on positive cytokeratin (CK) 5/6 and/or epidermal growth factor receptor (EGFR) expression. In particular, CK5/6 expression is reported to correlate with TNBC recurrence. TNBC lacks ER-α expression, but some TNBCs are known to express the androgen receptor (AR). Moreover, although p53 accumulation is detected in various malignant tumors, its influence on adjuvant chemotherapy for patients with TNBC remains unclear. The aim of this study was to assess the combined immunohistochemical expression of CK 5/6, AR, and p53 as a potential prognostic marker of adjuvant chemotherapy for patients with TNBC. The expression of CK5/6, AR, and p53 in formalin-fixed and paraffin-embedded (FFPE) surgical sections from 52 patients with TNBC was analysed by immunohistochemistry (IHC) and the co-expression patterns in individual cells were investigated by immunofluorescent (IF) staining. Low AR expression was correlated with high clinical stage (P < 0.05) and low nuclear grade (P < 0.05). The expression of CK5/6 and p53 did not correlate with clinicopathological features. Patients who needed adjuvant chemotherapy presented the worst prognosis. In particular, when the IHC expression pattern was CK5/6 (-), AR (-), and p53 (+), the disease free survival (DFS) and overall survival (OS) were the worst. On the other hand, patients with AR (+) and p53 (-) TNBC presented a good prognosis. The analysis of the co-expression status of these three markers showed that no cells presented both AR and CK5/6 expression. Furthermore, TP53 mRNA expression was higher in patients with AR-negative TNBC (P < 0.05) and in patients with the worst prognosis (P < 0.05) than in the other patients. These results suggested that, in patients with CK5/6-negative TNBC, AR expression correlated with good prognosis, but p53 accumulation correlated with poor prognosis. The present IHC markers allowed us to predict the post-surgery prognosis of patients with TNBC. In conclusion, TNBCs are heterogeneous. Patients with the CK5/6 (-), AR (-), and p53 (+) TNBC subtype, evaluated by IHC, presented the worst prognosis. These IHC markers will be helpful to follow patients with TNBC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer

et al. 2015

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“…The majority of studies investigating the relationship between AR levels in the primary tumour, clinical characteristics and disease outcome have found that AR expression is a favourable prognostic indicator (reviewed by Hickey et al (2012)). In cohorts not selected on the basis of estrogen receptor-a (ERa (ESR1)) status, AR positivity has been associated with longer relapse-free, metastasis-free and overall survival, smaller tumour size and lower histological grade (Bryan et al 1984, Langer et al 1990, Kuenen-Boumeester et al 1992, Soreide et al 1992, Schippinger et al 2006, Agrawal et al 2008, Gonzalez et al 2008, Hanley et al 2008, Ogawa et al 2008, Soiland et al 2008, Park et al 2010, Yu et al 2011, Peters et al 2012, Honma et al 2013. High AR levels have also been associated with a favourable response to chemotherapy and hormonal therapy, including antioestrogens, aromatase inhibitors and progestins (Teulings et al 1980, Bryan et al 1984, Birrell et al 1995, Agrawal et al 2008, Chintamani et al 2010, Chanplakorn et al 2011, Loibl et al 2011.…”

Section: Prognostic Value Of Ar Expression In Breast Cancermentioning

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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“…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). What is unclear, however, is the mechanism by which androgens influence hormonal sensitivity and disease progression in breast cancer and how best to use AR signaling to modulate the growth of breast cancer cells (9,14). In this study, we show that the AR level is significantly associated with disease outcome in ERapositive breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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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Lack of expression of androgen receptor may play a critical role in transformation from in situ to invasive basal subtype of high-grade ductal carcinoma of the breast

Cited by 59 publications

References 31 publications

Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer

Immunohistochemical co-expression status of cytokeratin 5/6, androgen receptor, and p53 as prognostic factors of adjuvant chemotherapy for triple negative breast cancer

Complexities of androgen receptor signalling in breast cancer

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

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