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Background  The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BK Ca ) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of  KCNMA1  gene that encodes for the pore-forming α-subunit of BK Ca  channels in breast cancer metastasis and invasion.    Methods  We performed Global exon array to study the expression of  KCNMA1  in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BK Ca  channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BK Ca  channel inhibition attenuates breast tumor invasion and metastasis using  KCNMA1  knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX).    Results  The Global exon array and RT-PCR showed higher  KCNMA1  expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BK Ca  channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking  KCNMA1 .    Conclusion  Determining the relative abundance of BK Ca  channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.

Role of KCNMA1gene in breast cancer invasion and metastasis to brain