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An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen


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.

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We thank Dr Dennis Watson for generously providing SPDEF antibody, Yixin Wang and John A Foekens for providing unpublished data, Adam Olshen and Gaorav Gupta for advice and manuscript review, Louis Vargus, Yonghong Xiao and Lishi Chen for technical assistance, Andea Aleodor for histological analysis and Faye Taylor for data management. We are indebted to the Pathology and Genomics Core Facilities at MSKCC for technical support. WG was supported by DAMD BC010104.

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Correspondence to W L Gerald.

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Doane, A., Danso, M., Lal, P. et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 25, 3994–4008 (2006).

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  • breast cancer
  • estrogen receptor-negative
  • ndrogen responsive
  • gene expression

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