Androgens and androgen receptors in breast cancer

Díaz-Chico, B.N.; Rodrìguez, Fernando; González, Ana; Ramírez, Raquel; Bilbao, Cristina; León, Antonio Cabrera de; Jaime, Armando Aguirre; Chirino, Ricardo; Navarro, Domingo; Díaz-Chico, J. C.

doi:10.1016/j.jsbmb.2006.11.019

Cited by 96 publications

(51 citation statements)

References 100 publications

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“…The exact role of androgen in breast cancer development, prognosis and therapy has been in the center of significant controversies; this is partly due to different applied methodologies, with their focus on different androgen molecules and different groups of patients [2]. Some studies have identified significant correlations between high testosterone levels and breast cancer development in pre-menopausal women.…”

Section: Introductionmentioning

confidence: 99%

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Azariadis¹,

Kiagiadaki

Pelekanou³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines. Methods: We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases. Results: CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases. Conclusion: AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors.

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Section: Introductionmentioning

confidence: 99%

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Azariadis¹,

Kiagiadaki

Pelekanou³

et al. 2017

Cell Physiol Biochem

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“…In women, sex steroid hormones are produced by the ovaries (and adrenal glands in the case of androgens) and through peripheral conversion of circulating precursors (Simpson 2003, Nicolas Diaz-Chico et al 2007, McNamara et al 2014, McNamara & Sasano 2015. SSRs are structurally related and evolutionarily conserved, have similar consensus DNA-binding motifs and use common co-factors for activity (Germain et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Pushing estrogen receptor around in breast cancer

Lim

Tarulli

Portman

et al. 2016

Endocrine-Related Cancer

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The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to 'push' ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.

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“…Importantly, a characteristic steroid receptor expression profile further defines these tumors as consistently estrogen receptor (ER) negative, progesterone receptor (PR) negative and androgen receptor (AR) positive. [4][5][6][7][8] Although AR expression has been variably observed in up to 60-70% breast carcinomas, 9,10 consistent AR expression tends to be a feature of apocrine breast lesions including invasive apocrine carcinomas. 4,5,8,11,12 Moreover, recently published gene expression microarray studies defined a characteristic 'molecular apocrine' gene expression profile found in apocrine carcinomas.…”

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confidence: 99%

EGFR and HER-2/neu expression in invasive apocrine carcinoma of the breast

et al. 2010

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This study was undertaken to investigate epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2)/neu expression in a cohort of apocrine carcinomas of the breast with emphasis on the classification of the breast tumors with apocrine morphology. In total, 55 breast carcinomas morphologically diagnosed as apocrine were evaluated for the steroid receptor expression profile characteristic of normal apocrine epithelium (androgen receptor positive/estrogen receptor (ER) negative/progesterone receptor (PR) negative), and for the expression of EGFR and Her-2/neu proteins, and the copy number ratios of the genes EGFR/CEP7 and HER-2/CEP17. On the basis of the results of steroid receptors expression, 38 (69%) cases were classified as pure apocrine carcinoma (androgen receptor positive/ER negative/PR negative), whereas 17 (31%) were re-classified as apocrine-like carcinomas because they did not have the characteristic steroid receptor expression profile. Her-2/neu overexpression was observed in 54% of the cases (57% pure apocrine carcinomas vs 47% apocrine-like carcinomas). HER-2/neu gene amplification was demonstrated in 52% of all cases (54% pure apocrine carcinomas vs 46% apocrine-like carcinomas). EGFR protein (scores 1 to 3 þ ) was detected in 62% of all cases and was expressed in a higher proportion of pure apocrine carcinomas than in the apocrine-like carcinomas group (76 vs 29%, P ¼ 0.006). In the pure apocrine carcinoma group, Her-2/ neu and EGFR protein expression were inversely correlated (P ¼ 0.006, r ¼ À0.499). EGFR gene amplification was observed in two pure apocrine carcinomas and one apocrine-like carcinoma. Polysomy 7 was commonly present in pure apocrine carcinomas (61 vs 27% of apocrine-like carcinomas; P ¼ 0.083) and showed a weak positive correlation with EGFR protein expression (P ¼ 0.025, r ¼ 0.326). Our study showed that apocrine breast carcinomas are molecularly diverse group of carcinomas. Strictly defined pure apocrine carcinomas are either HER-2-overexpressing breast carcinomas or triple-negative breast carcinomas, whereas apocrine-like carcinomas predominantly belong to the luminal phenotype. Pure apocrine carcinomas show consistent overexpression of either EGFR or HER-2/neu, which could have significant therapeutic implications.

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Androgens and androgen receptors in breast cancer

Cited by 96 publications

References 100 publications

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

Pushing estrogen receptor around in breast cancer

EGFR and HER-2/neu expression in invasive apocrine carcinoma of the breast

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