Store-operated Ca2+ influx is known to be involved in cancer cell migra-tion, but the finer molecular details of this process have yet to be mapped out. Xin-Yun Huang and colleagues have investigated the function of two known regulators of Ca2+ influx and found their function to be essential for breast cancer metastasis.

ORAI1 (also known as CRACM1) and stromal interaction molecule 1 (STIM1) are involved in regulating store-operated Ca2+ influx in non-excitable cells: STIM1 is a Ca2+ sensor and ORAI1 is part of the pore that enables store-operated Ca2+ entry. On testing a variety of inhibitors of ion channels that enable Ca2+ influx, the authors found that the inhibition of store-operated channels suppressed serum-induced cell migration. Further experiments using small interfering RNAs (siRNAs) to target STIM1 or ORAI1 indicated that these proteins are required for the migration of MDA-MB-231 human breast tumour cells in vitro.

Why do cells with reduced levels of ORAI1 and STIM1 have impaired migration? Further analyses showed that the assembly and disassembly of focal adhesions, which are known to be crucial for cellular migration, were blocked in these cells. This defect could be overcome by the expression of either constitutively active Ras or RAC1. Moreover, expression of active RAC1 was able to overcome the migration defect induced by siRNAs to either ORAI1 or STIM1.

To extend these in vitro findings the authors carried out tail vein injec-tions of MDA-MB-231 cells express-ing siRNAs targeting either STIM1 or ORAI1 or control siRNAs. The control cells proliferated in the lungs, where they become lodged after injection, whereas those expressing reduced lev-els of either STIM1 or ORAI1 showed significantly lower levels of metastatic growth. Importantly, the authors also showed that SKF96365, a pharma-cological inhibitor of store-operated Ca2+ channels, reduced metastatic

growth of 4T1 mouse breast cancer cells after orthotopic injection in syngeneic mice.

Thus, STIM1 and ORAI1 are potential new targets for the inhibition of breast cancer cell migration and metastasis owing to their involvement in regulating focal adhesion turnover.

Nicola McCarthy

ORIGINAL RESEARCH PAPER Yang, S., Zhang, J. J. & Huang, X.-Y. Orai1 and STIM1 are critical for breast cancer cell migration and metastasis. Cancer Cell 15, 124–134 (2009)

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Calcium influx is moving

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NATuRe RevIeWS | CanCer vOluMe 9 | ApRIl 2009

Nature Reviews Cancer | AOp, published online 12 March 2009; doi:10.1038/nrc2629

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