Estradiol Regulation of Leucine-Rich Repeat Immunoglobulinlike Domains Protein 1 (Lrig 1) and Roles of Estrogen Receptor in Translational Regulation in Breast Cancer Cells
The effects of estradiol on cellular function are pleiotropic. As a transcriptional regulator, ER regulates many genes that can have a subsequent impact on other cellular functions. These so-called secondary effects are often associated as the principle actions of estradiol. We identify leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) as an estradiol-regulated gene. LRIG1 is a negative regulator of Receptor Tyrosine Kinase (RTK) signaling. Up-regulation of LRIG1 mRNA and protein is mediated by the estrogen receptor-alpha (ERalpha) and we identified the regions of the LRIG1 gene to which ER binds. LRIG1 regulation by estradiol helps to explain how tumors typically utilize either estradiol or growth factor pathways, but rarely both, as mitogenic stimuli. Increased LRIG1, in response to estradiol, results in decreased signaling through RTK pathways. The impact of LRIG1 regulation by estradiol is cell-type specific. LRIG1 protein levels are important for both the growth of cells as well as colony formation and invasiveness of ERalpha-positive and HER2-positive BT-474 and ERalpha-positive and HER2-negative MCF-7 breast cancer cell lines. LRIG1 regulation by estradiol may be important for breast cancer etiology and phenotypic properties by influencing signaling pathways such as the AKT and MAPK pathways, which help to determine the breast tumor subtype as well as responsiveness to cancer treatments.
University of Illinois - Urbana-Champaign
Networked Digital Library of Theses and Dissertations
University of Illinois at Urbana-Champaign