Minireview: The androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene?

Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer.     

Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer

High androgen receptor (AR) level in primary tumour predicts increased prostate cancer-specific mortality. However, the mechanisms that regulate AR function in prostate cancer are poorly known. We report here a new paradigm for the forkhead protein FoxA1 action in androgen signalling. Besides pioneering the AR pathway, FoxA1 depletion elicited extensive redistribution of AR-binding sites (ARBs) on LNCaP-1F5 cell chromatin that was commensurate with changes in androgen-dependent gene expression signature. We identified three distinct classes of ARBs and androgen-responsive genes: (i) independent of FoxA1, (ii) pioneered by FoxA1 and (iii) masked by FoxA1 and functional upon FoxA1 depletion. FoxA1 depletion also reprogrammed AR binding in VCaP cells, and glucocorticoid receptor binding and glucocorticoid-dependent signalling in LNCaP-1F5 cells. Importantly, FoxA1 protein level in primary prostate tumour had significant association to disease outcome; high FoxA1 level was associated with poor prognosis, whereas low FoxA1 level, even in the presence of high AR expression, predicted good prognosis. The role of FoxA1 in androgen signalling and prostate cancer is distinctly different from that in oestrogen signalling and breast cancer.     

Epidermal growth factor receptors in breast cancer: association with early relapse and death, poor response to hormones and interactions with neu

Epidermal growth factor receptors (EGFRs) were measured in 221 primary breast cancers by ligand binding with 125I-labelled EGF, and high-affinity sites were quantitated. There was a highly significant inverse relationship between oestrogen receptor (ER) and EGFR (15 EGFR-positive [EGFR+]ER+ and 92 EGFR-negative [EGFR-]ER+: 54 EGFR- ER- and 60 EGFR+ ER-). The relapse-free survival and overall survival were significantly shorter for EGFR+ vs EGFR- tumours (P less than 0.001) by about 2 yr in the case of relapse-free survival. When ER- tumours were substratified by EGFR status, the EGFR- ER- tumours had a prognosis almost as good as the ER+ tumours. In 31 of 184 cases, high expression of neu, correlating with amplification, was found. Expression of neu conferred similar poor prognosis to EGFR expression in all prognostic subgroups. Coexpression of neu and EGFR had an additive adverse effect. Epidermal growth factor receptors (EGFR) and oestrogen receptors (ER) were analysed in 221 patients with primary operable breast cancer by means of radioligand assays. After median follow-up of 24 months (range 3-60 months), there had been recurrences in 99 patients, of whom 72 (median age 56 yr, range 32-77 yr) received tamoxifen alone as first-line treatment for recurrence. 14 patients (19%) showed a response to this therapy and 58 (81%) did not. Of 32 ER+ tumours, 12 (37.5%) showed an objective response to tamoxifen compared with only 2 of 40 (5%) ER- tumours (P less than 0.005). Of 35 EGFR+ tumours, 3 (8.5%) achieved an objective response compared with 11 of 36 (30%) EGFR tumours (P less than 0.05). Only 1 of 28 EGFR+, ER- tumours achieved an objective response. Including patients whose disease remained stable for more than 6 months with the responders, however, EGFR status was a better predictor of response to tamoxifen; 15 of 37 EGFR- patients and 5 of 35 EGFR+ patients responded (P less than 0.01).     

Expression of oestrogen receptor-beta in invasive breast tumours

Steroid hormone receptors are used routinely to predict endocrine responsiveness in patients with breast cancer. Two oestrogen receptors (ERs): ER alpha and ER beta have been identified. Although ER alpha and ER beta genes share a large degree of homology, it is generally thought that their distribution and function are substantially different in many tissues. Both of them may be expressed in normal and neoplastic tissues of the breast. While much is known about ER alpha, the role of ER beta is still undefined, especially at the protein level. Recent development of reliable antibodies to ER beta has provided opportunity to test immunohistochemical reactions detecting ER beta in archival breast tumours. The aim of our study was to learn more about the cellular mechanisms underlying the relationship of ER beta and progesterone receptor (PR) in breast cancer tissues, discriminating between hormone-dependent and hormone-independent tumours. ER alpha and PR content of tumour tissues of 154 patients with breast cancer were tested by in situ indirect immunohistochemical method parallel with ligand binding biochemical assay. ER beta was detected in 8 ER alpha-/PR+ breast carcinomas by immunohistochemical method too. Steroid hormone receptor content was analysed comparing to the histologic type and grading of the tumours. CONCLUSIONS: A considerable part of breast carcinomas belongs to the ER+/PR+ and ER-/PR- groups. About 1-2% of the tumours is expected to be ER alpha-/ER beta+/PR+ type. In such cases ER alpha negative reaction together with PR positivity can signal the necessity of the immunohistochemical detection of ER beta in routine histopathological practice, presenting the precise steroid hormone receptor status for the most effective endocrine therapy of the patients.     

S100A14在乳腺癌不同分子亚型中表达的临床病理研究

目的:探讨S100钙结合蛋白A14(S100A14)在乳腺癌不同分子亚型中的表达及临床病理意义,为确定新的分子分型标志物提供参考依据。方法:254例乳腺癌石蜡组织来源于2013年1月16日至2014年5月22日在中南大学湘雅医学院附属肿瘤医院暨湖南省肿瘤医院进行乳腺癌根治术的患者。应用免疫组织化学方法检测S100A14在乳腺癌组织中的表达,分析其S100A14在不同分子亚型乳腺癌组织中表达及其与患者临床病理指标间的相关性,采用Kaplan-Meier法分析S100A14蛋白表达与乳腺癌患者预后的关系。结果:S100A14在ER+/PR+/HER2+型、ER+/PR+/HER2-型、ER-/PR-/HER2+型、ER-/PR-/HER2-型乳腺癌四种分子亚型中的阳性表达分别为38.5%、47.1%、75.5%、80.0%,以在ER-/PR-/HER2-型中表达最高,在ER+/PR+/HER2+型中表达最低,四组间的阳性表达比较差异有显著统计学意义(P0.01);S100A14的表达与乳腺癌患者术后肝转移呈正相关(r=0.134,P0.05),与ER、PR表达均呈负相关(r=-0.353,P0.01),而与ER+/PR+/HER2+型、ER+/PR+/HER2-型乳腺癌的临床病理特征无显著相关性(P0.05)。在ER-/PR-/HER2+型乳腺癌中,有腋窝淋巴结转移组患者的S100A14阳性表达率明显高于无腋窝淋巴结转移组,差异有统计学意义(P0.05);在ER-/PR-/HER2-型中,S100A14表达与术后肺转移呈负相关(r=-0.272, P=0.044)。结论:S100A14在不同分子亚型乳腺癌中表达存在差异,其表达与不同分子类型乳腺癌转移或复发有关,可能作为乳腺癌分子分型的候选标记物。     

Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines.

Lack of estrogen receptor (ER) and presence of vimentin (VIM) associate with poor prognosis in human breast cancer. We have explored the relationships between ER, VIM, and invasiveness in human breast cancer cell lines. In the matrigel outgrowth assay, ER+/VIM- (MCF-7, T47D, ZR-75-1), and ER-/VIM- (MDA-MB-468, SK-Br-3) cell lines were uninvasive, while ER-/VIM+ (BT549, MDA-MB-231, MDA-MB-435, MDA-MB-436, Hs578T) lines formed invasive, penetrating colonies. Similarly, ER-/VIM+ cell lines were significantly more invasive than either the ER+/VIM- or ER-/VIM- cell lines in the Boyden chamber chemoinvasion assay. Invasive activity in nude mice was only seen with ER-/VIM+ cell lines MDA-MB-231, MDA-MB-435 and MDA-MB-436. Hs578T cells (ER-/VIM+) showed hematogenous dissemination to the lungs in one of five mice, but lacked local invasion. The ER-/VIM+ MCF-7ADR subline was significantly more active than the MCF-7 cells in vitro, but resembled the wild-type MCF-7 parent in in vivo activity. Data from these cell lines suggest that human breast cancer progression results first in the loss of ER, and subsequently in VIM acquisition, the latter being associated with increased metastatic potential through enhanced invasiveness. The MCF-7ADR data provide evidence that this transition can occur in human breast cancer cells. Vimentin expression may provide useful insights into mechanisms of invasion and/or breast cancer cell progression.