Targeting CaSR/GABAB R1 Heterodimers to Treat Bone Metastases in Breast Cancer
Abstract
The goal of this project are to test whether genetic or pharmacologic inhibition of CaSR/GABAB R1 heterodimers can antagonize the growth and/or survival of breast cancer cells exposed to high extracellular calcium in vitro or grown in animal models of bone metastases in vivo. In the first year, we have made considerable progress in achieving goals in Aims 1 and 2. We found that knocking down CaSR expression or inhibiting CaSR function with the calcilytic compound, NPS-2146, in breast cancer cells resulted in a reduction in the cAMP and PTHrP responses to high extracellular calcium levels. It also blunted proliferation and increased calcium-induced apoptosis. These changes in cell turnover were accompanied by an increase in p27 levels and an increase in nuclear AIF levels. We have generated stable GABABR1-knockdown MDA-MB231.1866 cells and are beginning to characterize their responses in the same manner as the CaSR-knockdown cells. We have also begun to examine how inhibition of the CaSR and GABABR1 may sensitize cancer cells to DNA damaging agents
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2017
- Accession Number
- AD1054030
Entities
People
- John Wysolmerski
Organizations
- Yale University