A functional role for T-type calcium channels in breast cancer cell proliferation.

摘要

Breast cancer is a disease that affects the length and quality of life of many women. It has been suggested that T-type calcium channels play a role in proliferation in various cancer cell types, including breast cancer. However, the details of that role have not been examined adequately. We used a common model for breast cancer, the MCF-7 cell line, to examine T-type calcium channel expression in breast cancer cells and the effects of inhibiting T-type calcium channels on breast cancer cell growth. We found that T-type calcium channels were expressed in non-confluent MCF-7 monolayers, but that expression was greatly diminished in confluent monolayers. We also show that blocking T-type calcium channels with the mibefradil derivative NNC-55-0396 and reducing functional expression of the channels with RNA interference both significantly inhibit MCF-7 cell growth, with no significant loss of viability. We show evidence that reducing extracellular calcium concentration with EGTA results in a dose-dependent reduction in MCF-7 cell growth. We found that blocking T-type calcium channels with mibefradil reduces MCF-7 intracellular calcium concentration as measured by fura-2 fluorescence microscopy. The importance of intracellular calcium stores is shown by our findings that the SERCA inhibitor thapsigargin causes a reduction in MCF-7 cell growth in dose-dependent and time-dependent manners. Our findings include evidence that mibefradil induces an increased expression of the tumor suppressor p21, as has been found in other cancer types. Finally, we show that T-type calcium channel blockers used in alternation with paclitaxel chemotherapy against MCF-7 cells yields better results better results than chemotherapy alone, both in vitro and in an in vivo mouse model. These results help firmly establish a functional role for T-type calcium channels in MCF-7 breast cancer cell growth, and emphasize the importance of T-type calcium channels as a possible target in breast cancer therapy.