An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen
An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen
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DOI：
10.1038/sj.onc.1209415
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发表时间：
2006-06-01
期刊：
影响因子：
8
通讯作者：
Gerald, W. L.
中科院分区：
文献类型：
--
作者：
Doane, A. S.;Danso, M.;Gerald, W. L.
雌激素受体阴性、孕激素受体阴性（ER（-）/PR（-））乳腺癌（BC）的潜在生物学知之甚少，并且几乎没有靶向治疗。ER（-）/ PR（-）肿瘤的临床异质性表明存在分子亚群。我们对99个原发性BC样本和8个BC细胞系进行了全基因组表达分析，以揭示不同的亚群，深入了解其生物学，并可能识别新的治疗靶点。我们鉴定了一组ER（-）/PR（-）肿瘤，其基因表达矛盾，已知这些基因要么是ER的直接靶点，对雌激素有反应，要么通常在ER（+）BC中表达。差异表达的基因有SPDEF、FOXA 1、XBP 1、CYB 5、TFF 3、NAT 1、APOD、ALCAM和AR（P < 0.001）。基于该肿瘤类别的表达特征的分类模型在独立的人BC数据集中和BC细胞系（MDA-MB 453）中鉴定了分子相似的BC。该细胞系表现出对雄激素的增殖反应，雄激素受体依赖性和ER非依赖性的方式。此外，雄激素诱导的MDA-MB-453转录程序与人类肿瘤独特的ER（-）/PR（-）亚类的分子特征显著重叠。这一亚群的BCs，其特征在于一个神经调节的转录程序和雄激素的反应，表明潜在的治疗策略，针对雄激素信号通路。
Little is known of the underlying biology of estrogen receptor-negative, progesterone receptor-negative (ER(-)/PR(-)) breast cancer (BC), and few targeted therapies are available. Clinical heterogeneity of ER(-)/ PR(-) tumors suggests that molecular subsets exist. We performed genome-wide expression analysis of 99 primary BC samples and eight BC cell lines in an effort to reveal distinct subsets, provide insight into their biology and potentially identify new therapeutic targets. We identified a subset of ER(-)/PR(-) tumors with paradoxical expression of genes known to be either direct targets of ER, responsive to estrogen, or typically expressed in ER(+) BC. Differentially expressed genes included SPDEF, FOXA1, XBP1, CYB5, TFF3, NAT1, APOD, ALCAM and AR (P < 0.001). A classification model based on the expression signature of this tumor class identified molecularly similar BCs in an independent human BC data set and among BC cell lines (MDA-MB453). This cell line demonstrated a proliferative response to androgen in an androgen receptor-dependent and ER-independent manner. In addition, the androgen-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of the unique ER(-)/PR(-) subclass of human tumors. This subset of BCs, characterized by a hormonally regulated transcriptional program and response to androgen, suggests the potential for therapeutic strategies targeting the androgen signaling pathway.