Doane A S, Danso M, Lal P, Donaton M, Zhang L, Hudis C, Gerald W L
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Oncogene. 2006 Jun 29;25(28):3994-4008. doi: 10.1038/sj.onc.1209415. Epub 2006 Feb 20.
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-MB-453). 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.
雌激素受体阴性、孕激素受体阴性（ER(-)/PR(-)）乳腺癌（BC）的潜在生物学特性鲜为人知，且可用的靶向治疗方法很少。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，深入了解其生物学特性，并潜在地确定新的治疗靶点。我们鉴定出了一个ER(-)/PR(-)肿瘤亚群，其具有已知为ER直接靶点、对雌激素有反应或通常在ER(+) BC中表达的基因的矛盾表达。差异表达的基因包括SPDEF、FOXA1、XBP1、CYB5、TFF3、NAT1、APOD、ALCAM和AR（P<0.001）。基于该肿瘤类表达特征的分类模型在一个独立的人类BC数据集中以及BC细胞系（MDA-MB-453）中鉴定出了分子相似的BC。该细胞系以雄激素受体依赖性和ER非依赖性方式对雄激素表现出增殖反应。此外，MDA-MB-453的雄激素诱导转录程序与人肿瘤独特的ER(-)/PR(-)亚类的分子特征显著重叠。这一BC亚群以激素调节的转录程序和对雄激素的反应为特征，提示了针对雄激素信号通路的治疗策略的潜力。
