Abstract A132: The HER4 intracellular domain (4ICD) functions as a potent estrogen receptor coactivator mediating estrogen stimulated proliferation of breast tumor cells

Abstract

Abstract Among women with breast cancer more than 70% present with tumors expressing the estrogen receptor (ER) and will be treated with a therapeutic combination that includes endocrine therapy. Unfortunately, over 50% of these women fail therapy and develop incurable and often lethal metastatic disease. Disengaging ER interactions with essential transcriptional coactivators represents an effective approach to suppress ER driven breast cancer. To this end we have identified the HER4 intracellular domain (4ICD) as a potent estrogen receptor coactivator modulating estrogen induced gene expression and mediating estrogen stimulated proliferation of breast tumor cells. In multiple clinical studies, HER4 expression is significantly associated with ER positive tumors with up to 90% of ER positive breast tumors coexpressing HER4. These clinical observations imply a strong tumor cell selection for HER4 and ER coexpression. Estrogen stimulation of the ER and HER4 positive MCF-7 breast tumor cell line results in proteolytic processing of HER4 to release 4ICD. Significantly, estrogen stimulates nuclear translocation and binding of the 4ICD/ER complex to promoters containing estrogen response elements. Here we performed microarray gene expression analysis comparing MCF-7 cells with endogenous HER4 expression to MCF-7 cells where HER4 was stably suppressed. We found that estrogen significantly stimulated expression (2 fold and above) of 786 genes and 399 (51%) of these genes also required HER4 expression. Furthermore, chromatin immunoprecipitation (ChIP) analysis of two ER-inducible genes, progesterone receptor (PgR) and stromal-derived factor 1 (SDF-1) shows that 4ICD binds to PgR and SDF-1 gene promoters suggesting that it is required for efficient promoter binding of ER to certain ER-mediated genes. These results clearly indicate that 4ICD is an important ER coactivator that enhances ER promoter interactions. Finally, we have evidence that HER4/4ICD is required for estrogen stimulated tumor cell proliferation raising the possibility that disrupting the interaction between 4ICD and ER would represent a novel therapeutic approach to suppress breast tumorigenesis. In the future, we propose to identify additional transcription factors recruited with the ER/4ICD genomic complex. Citation Format: Wen Han, Frank Jones. The HER4 intracellular domain (4ICD) functions as a potent estrogen receptor coactivator mediating estrogen stimulated proliferation of breast tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A132.