BRMS1 Suppresses Breast Cancer Metastasis to Bone via Its Regulation of MicroRNA-125b and Downstream Attenuation of TNF-alpha and HER2 Signaling Pathways
Abstract
Human breast cancer cells with restored BRMS1 expression exhibit few in vitro changes when compared to control cells, but demonstrate a very strong suppression of metastasis in in vivo animal models of breast cancer and several other solid tumor types. We have previously shown that in tissue samples collected from breast cancer patients, there exists an inverse correlation between expression of BRMS1 and HER2, an important druggable target in breast cancer. HER2 expression and function are particularly important in the context of inflammatory breast cancer, where up to 60% of all tumors are HER2+, but usually negative for hormone receptors ER and PR. Patients with inflammatory breast cancer have few treatment options and have one of the highest metastatic relapse rate and lowest survival among all breast cancer patients. In Year 1 progress report, we identified KPL4 inflammatory breast cancer cell line as a good candidate for reexpression of BRMS1, since there is HER2 amplification and cells were described in the literature as spontaneously metastatic. In the studies described below, we identified several novel BRMS1-interacting partners, such as AMPK, a major kinase regulating cellular metabolism, and Filamin B, a cytoplasmic protein that participates in cellular adhesion and motility. We also determined that BRMS1 can be phosphorylated on a single Serine residue and that this phosphorylation sites lies within an AMPK consensus sequence. Finally, we determined that BRMS1-expressing cells exhibit a decreased level of phosphorylated STAT3, leading to modulation in expression of proapoptotic genes. However, based on new data, we identified a non-cononical mechanism responsible for decreased STAT3 phosphorylation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2013
- Accession Number
- ADA594028
Entities
People
- Mien-Chie Hung
- Yekaterina B. Khotskaya
Organizations
- The University of Texas MD Anderson Cancer Center