Talk abstracts
Talk on Tuesday 03:15-03:30pm submitted by Corinne Haines
Investigating the role of GREB1 in clathrin-mediated endocytosis and proliferation
Corinne N. Haines (MCDB), Craig Burd (Molecular Genetics)
Abstract:
Over 70% of human breast cancers express the estrogen receptor (ER) and depend on ER activity for survival and proliferation. Patients diagnosed with ER-positive breast cancer are treated with hormone therapies that target receptor activity. However, tumors invariably develop resistance highlighting the need for new and innovative therapies. While the mechanism in which ER regulates proliferation is poorly understood, one gene target of ER, growth regulation by estrogen in breast cancer 1 (GREB1), has been implicated in mediation of this signal. GREB1 is highly correlated with proliferation in estrogen responsive breast cancer cells and loss of GREB1 in ER-dependent cell lines results in growth arrest, making it an attractive therapeutic target. Despite the relationship between GREB1 and estrogen-induced proliferation of breast cancer cells, the molecular functions of GREB1 have been largely uncharacterized. Published reports suggest GREB1 may feedback to regulate ER activity and thus control proliferation. However, we have shown that GREB1 is also able to regulate proliferation in ER-negative breast cancer cell lines, indicating an ER-independent function of GREB1. In these cell lines, we have shown that GREB1 overexpression induces the activation of p38, a driver of oncogene-induced senescence. Interestingly, p38 also has an emerging role in the regulation of clathrin-mediated endocytosis (CME) of receptors such as EGFR. Using mass spectrometry, we have identified many proteins involved in CME and substrates of EGFR as GREB1 interactors, further supporting a role for GREB1 in this process. Using immunofluorescence microscopy, we have shown that nuclear GREB1 rapidly re-localizes to the cytoplasm upon stimulation of CME with EGF such that is poised to participate in this internalization of EGFR. These data suggest an emerging role of GREB1 in the regulation of CME and a potential mechanism by which GREB1 regulates proliferation in breast cancer, ultimately bringing the field closer to using GREB1 as a therapeutic target.
Keywords: breast cancer , endocytosis, GREB1