Abstract 5313: Sustained hypercalcemia primes non-invasive breast cancer cells for metastasis to high calcium microenvironments

Abstract

Abstract Breast cancer frequently spreads to calcium-rich organs/metastatic sites such as skeletal tissues but the role of hypercalcemia in breast cancer progression remains poorly understood. While patients with metastatic or end-stage cancer are likely to become hypercalcemic, up to 30% of breast cancer patients develop cancer-induced hypercalcemia (CIH) in the absence of metastases or bone diseases. The resulting high extracellular ionized calcium (Ca2+) activates the calcium sensing receptor (CaSR) that not only promotes the proliferation of breast cancer cells but also the secretion of parathyroid hormone-related protein by the tumor cells. This suggests that CIH may promote both the vicious osteolytic cycle and breast cancer progression. In this study, we examined whether sustained hypercalcemia primes breast cancer cells for metastasis to high Ca2+ microenvironments. We demonstrate that sustained hypercalcemia enables Ca2+-sensitive non invasive breast cancer cells such as MCF-7 to become high Ca2+-adapted and that this adaptation is accompanied by increased motility and more aggressive growth (increased proliferation). Consistent with this observation, invasive and metastatic breast cancer cells are high Ca2+-adapted cells that efficiently grow over a wide range of Ca2+ concentrations (up to 10 mM). Interestingly, we also show that at high Ca2+ (5 mM) breast cancer cells expressing the Q1011E CaSR variant that is common among African Americans proliferate faster than those expressing the A986S CaSR variant that is common among Caucasians. These data suggest that differences in the adaptation of breast cancer cells to hypercalcemia due in part to the expression of distinct CaSR variants underlie the distinct race-related breast cancer outcomes. This work is funded by the following grants made available to JO: DOD-W81XWH-07-1-0254 and 1SC1CA134018-01 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5313. doi:1538-7445.AM2012-5313