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BRMS1 modulation of EGF-receptor signaling
Metastasis suppressor genes, by definition, suppress metastasis without affecting tumorigenesis. The metastasis suppressor gene Breast cancer Metastasis Suppressor 1 (BRMS1) has been shown to suppress metastatic ability of breast cancer and melanoma cell lines without affecting tumorigenesis. Recent studies indicate that BRMS1 may control gene regulation through association with histone deacetylases. However, the mechanisms underlying BRMS1-mediated metastasis suppression are still poorly defined. Tumor cells are critically dependent on stimuli from the microenvironment for their growth, and receptors such as the Epidermal Growth Factor (EGF) receptor are important transducers of external growth signals. Preliminary results show EGF-receptor protein levels to be significantly reduced in MDA-MB-231 (231) cells stably transfected with BRMS1. Further, levels of EGFR correlate inversely with the level of BRMS1 in 231BRMS1 clones. The central hypothesis is that expression of BRMS1 reduces EGFR expression affecting downstream signaling through the receptor, thus reducing the metastatic potential of breast cancer cells. This hypothesis will be tested as follows: Specific Aim 1 will evaluate effects of BRMS1 expression on EGFR levels (and family members) in breast cancer cells of varying metastatic potential and with an inducible BRMS1 system to determine if a threshold level of BRMS1 is required for EGFR downregulation. Modulation of EGFR expression by BRMS1 will be characterized by promoter-reporter assays, mRNA, protein analysis. Specific Aim 2 will address changes in signaling downstream of EGFR, focusing on the PI3-kinase pathway, following stimulation with agonists (EGF, Heregulin, and Amphiregulin). Since BRMS1 affects EGFR expression, it will be assessed in vitro if loss of EGFR alters chemosensitivity to EGFR antagonists and representative anti-cancer agents. Specific Aim 3 will involve decreasing EGFR levels in 231 cells using siRNA and in vivo metastasis assays to answer the question whether loss of EGFR expression alone (in the absence of BRMS1) is sufficient to suppress metastasis. This outlined research will give critical insights into the mechanisms of action of metastasis suppressor genes, especially BRMS1.
Most of the mortality and morbidity associated with breast cancer is due to metastatic disease. Therefore, control of metastatic spread is expected to reduce mortality and significantly improve quality of life. Metastasis suppressor genes are defined a class of genes that do not block growth of the primary tumor itself, but prevent growth of tumors at the secondary site. Since breast tumor cells expressing the metastasis suppressor gene BRMS1 (Breast cancer Metastasis Suppressor 1) grow in mammary tissue, but not lungs, the data suggests a differential response to signals from the local environment. The questions are: what are the signals and what is changed in tumor cells, that alters their response. The ultimate goal of this project is to ask why BRMS1 allows growth of mammary tumors but not lungs. We previously found a change in signaling occurring in BRMS1 expressing cells which raised the question whether there might be a change in upstream receptors. We found that Epidermal Growth Factor Receptor (EGFR) levels were significantly reduced in BRMS1 expressing cells. The specific objective of this proposal is to follow up on those observations. We will more critically define the molecular relationship(s) between BRMS1 and EGFR (and related family members). We will also directly test whether changes in EGFR levels alter signaling through previously implicated pathways. Finally, we will determine whether changes in EGFR levels are coincidental versus critical for BRMS1-mediated metastasis suppression. The proposed research will not only enable a better understanding of the metastatic process, but also identify novel therapeutic targets and aid in the development of better pharmaceutical agents to control metastatic disease.