Abstract 4755: Estrogen receptor mediates novel mechanisms of estrogen-induced growth and tamoxifen resistance in invasive lobular carcinoma

Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer representing ∼10% of newly diagnosed breast tumors. Over 90% of ILC cases are ER-positive, however, endocrine response and estrogen signaling are not well described in ILC. Retrospective analyses suggest that ILC patients treated with endocrine therapy have poorer outcomes than invasive ductal carcinoma (IDC) patients with similar biomarkers, and that ILC patients may not benefit from adjuvant tamoxifen. Additionally, we have recently identified ILC-specific ER-target genes and de novo tamoxifen resistance driven by ER in ILC model systems. Based on these observations, we hypothesize that ILC-specific signaling pathways driven by ER mediate growth and endocrine resistance in ILC cells. We focused on three putative mechanisms of endocrine response and resistance in ILC cells. First, we investigated the role of the Wnt signaling protein WNT4 in driving E2-induced growth. E2 induced ER binding at the WNT4 promoter and up-regulated expression specifically in ILC cells (versus IDC cells). As WNT4 has also been previously implicated in normal mammary gland growth and development, we hypothesize that ER-driven WNT4 expression of mediates E2-induced growth of ILC cells. Second, we investigated the role of the transcriptional repressor SNAI1 in ER-mediated gene expression and tamoxifen-resistance. SNAI1 gene expression was induced by both E2 and tamoxifen specifically in ILC cells, which paralleled unique pa...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Endocrinology Source Type: research