BRMS1 Suppresses Breast Cancer Metastasis to Bone via its Regulation of microRNA-125b and Downstream Attenuation of TNF-alpha and HER2 Signaling Pathways
Revised annual summary rept. 30 September 2011- 29 September 2012
M D ANDERSON CANCER CENTER HOUSTON TX
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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 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 re-expression of BRMS1, since there is HER2 amplification and cells were described in the literature as spontaneously metastatic. In the studies described below, we show that BRMS1 expression in these cells inhibits cell adhesion to several matrices, and preferentially suppresses metastasis to bone. We also begin to investigate molecular mechanisms responsible for inhibition of metastasis and identify Stat3 signaling as a potential driver signaling cascade.
- Medicine and Medical Research