Abstract A37: Cholesterol biosynthesis pathway as a novel mechanism of resistance identified in ER+ long-term estrogen deprived cells

Over 80% of breast cancers (BC) at primary diagnosis express the estrogen receptor (ER+). Therapies targeting the estrogenic stimulation of tumor growth reduce mortality from ER+ BC but resistance remains a major clinical problem. Data from large studies such as TCGA indicate that other than a small number of high frequency mutations such as TP53, PIK3CA and GATA3 that have little association with endocrine resistance, primary ER+ BC shows very low frequency of individual mutations making targeting difficult. In contrast, expression profiling of primary ER+ BC samples have identified several promising signatures/networks for targeting. In order to identify common adaptive mechanisms associated with resistance to aromatase inhibitors, we assessed changes in global gene expression during adaptation to long-term estrogen deprivation (LTED) in a panel of ER+ BC cell lines cultured in 2D on plastic (MCF7, T47D, HCC1428, SUM44, MDA-MB-361 and ZR75.1) or 3D on collagen to model the stromal compartment (MCF7). At the point of resistance MCF7-LTED, HCC1428-LTED and SUM44-LTED retained ER expression whilst T47D-LTED, ZR75.1-LTED and MDA-MB-361-LTED reduced or lost ER. In order to identify common adaptive mechanisms, ingenuity pathway was used. Genes submitted for analysis were selected on the basis of a p-value of 0.001, FDR 5% and fold change 1.5 relative to the parental cell lines. Strikingly, the cholesterol biosynthesis pathway was the common up-regulated pathway in the ER+ LTED ce...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Luminal Breast Cancer: Poster Presentations - Proffered Abstracts Source Type: research