Abstract 4755: Estrogen receptor mediates novel mechanisms of estrogen-induced growth and tamoxifen resistance in invasive lobular carcinoma
Authors: Sikora Matthew J. , Bahreini Amir , Oesterreich Steffi 
Published: May 2015

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 patterns of E2-mediated gene repression in ILC cells. Thus, SNAI1 may mediate E2-driven gene repression and tamoxifen resistance. Third, our prior identification of ILC-specific ER-target genes and ER-mediated tamoxifen resistance suggested that novel co-factors may associate with ER in ILC. We hypothesize that identification of these co-factors would provide novel targets for therapy in ILC.

Cell lines MDA MB 134VI and SUM44PE are used as in vitro models of ILC versus MCF-7 and T47D as models of IDC. siRNA-mediated knockdown of gene expression is utilized to assess the function of WNT4 and SNAI1. Cell proliferation and ER-target gene expression are assessed in both ILC and IDC models following knockdown. To identify novel ER co-factors in ILC, we co-immunoprecipitate ER with associated factors, and identify bound proteins by mass spectrometry.

Preliminary experiments have demonstrated that knockdown of either WNT4 or SNAI1 can suppress the growth of ILC cells, and that this effect is specific to ILC cells. Additionally, Co-IP/mass spec identifies co-factors that are specifically associated with ER in ILC cells. These observations suggest that unique ER-mediated signaling pathways drive endocrine response and resistance in ILC cells, and that further understanding of these pathways may present novel therapeutic targets in ILC.

Citation Format: Matthew J. Sikora, Amir Bahreini, Steffi Oesterreich. Estrogen receptor mediates novel mechanisms of estrogen-induced growth and tamoxifen resistance in invasive lobular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4755. doi:10.1158/1538-7445.AM2014-4755