Cytotoxic mechanisms of zoledronic acid in osteotropic breast cancer cells

Bone metastasis is the leading cause of death for breast cancer patients and causes decreased bone mass and severe pain. The bone is a hypoxic (low oxygen) microenvironment that can drive the spread of breast cancer cells by activating processes to enhance tumor cell survival and proliferation. Cancer cells disrupt the normal bone remodeling to favor bone breakdown. This process is combated clinically by Zoledronic acid (ZOL), a nitrogenous bisphosphonate drug, which suppresses bone metastases by inducing apoptosis of osteoclasts and cancer cells. While hypoxia dramatically modulates the processes of metastasis, angiogenesis, apoptosis and autophagy, it is not clear how inhibiting the angiogenic pathway (in hypoxia) by ZOL in breast cancer affects the induction of apoptosis. To address this issue, I used the invasive breast cancer cell line MDA-MB-231 and a metastatic clone that is known to invade bone (osteotropic) as our cellular model system and tested them under normal or hypoxic conditions. The hypothesis is that ZOL preferentially affects osteotropic breast cancer cells by decreasing angiogenesis and increasing apoptosis and that hypoxia decreases sensitivity to ZOL by counteracting these processes.