S2-6: ErbB3 Expression Is Required for Maintenance of Normal and Transformed Luminal Breast Epithelial Cells.

Abstract

Abstract The ErbB receptor tyrosine kinase family regulates breast development and cancer. ErbB2/HER2 expression correlates with HER2-enriched breast cancers, while epidermal growth factor receptor (EGFR) expression often correlates with triple negative breast cancers. Less is known regarding ErbB3, which harbors only weak kinase activity, but strongly activates phosphatidylinositol-3 kinase (PI3K)/Akt signaling upon heterodimerization with EGFR or ErbB2. We report herein that ERBB3 mRNA expression strongly correlates with Luminal A/B breast cancers, which express lower levels of EGFR and ErbB2. Mammary-specific loss of ErbB3 in mice reduced Akt phosphorylation and caused cell death in the luminal epithelium. A decreased luminal population in ErbB3-deficient epithelium correlated with expansion of the mammary stem/progenitor fraction. In normal breast samples, ERBB3 mRNA expression was highest in mature/progenitor luminal populations, and lowest in the stem/basal population. Loss of ErbB3 shifted gene expression in mammary epithelial cells to resemble a mammary stem cell signature. The genes most greatly impacted by ErbB3 loss produced a signature that correlated with decreased overall survival in tamoxifen-treated patients. Knock-down of ErbB3 in human luminal breast cancer cells caused decreased cell growth under conditions of estrogen deprivation, decreased expression of the gene encoding aromatase, and impaired expression of estrogen receptor-induced genes, including those that encode progesterone receptor and TFF1. Treatment of MCF7 luminal breast cancer xenografts with AMG-888, a humanized monoclonal antibody directed against ErbB3, decreased tumor growth. Combination of AMG-888 with the estrogen receptor inhibitor fulvestrant caused MCF7 tumor regression. Taken together, these results suggest that ErbB3 is required to sustain normal and transformed luminal epithelial cells of the breast, and suggest that targeting ErbB3 may improve the clinical outcome of breast cancers treated with endocrine therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-6.