Estrogen Receptor-Regulated Gene Signatures in Invasive Breast Cancer Cells and Aggressive Breast Tumors

SIMPLE SUMMARY: Metastatic breast cancer remains a major clinical problem, contributing to significant patient mortality, which is partly due to a lack of understanding around the early changes within the primary tumor. Tumors frequently become more aggressive and less treatable due to the activation of other signaling pathways, and, in ER+ disease, one of these pathways is NFκB. The coactivation of ER and NFκB (via IKKβ) promotes invasion and metastasis, and, here, we identify the signatures that are associated with these phenotypes. These signatures improve our understanding of how ER can drive aggressive disease, and may lead to the identification of key drivers, which could potentially be targeted with future therapies. ABSTRACT: Most metastatic breast cancers arise from estrogen receptor α (ER)-positive disease, and yet the role of ER in promoting metastasis is unclear. Here, we used an ER+ breast cancer cell line that is highly invasive in an ER- and IKKβ-dependent manner. We defined two ER-regulated gene signatures that are specifically regulated in the subpopulations of invasive cells. The first consists of proliferation-associated genes, which is a known function of ER, which actually suppress rather than enhance invasion. The second signature consists of genes involved in essential biological processes, such as organelle assembly and vesicle trafficking. Importantly, the second subpopulation-specific signature is associated with aggressive disease and poor patient outcome, independently of proliferation. These findings indicate a complex interplay between ER-driven proliferation and invasion, and they define new ER-regulated gene signatures that are predictive of aggressive ER+ breast cancer.