Role of KCNMA1gene in breast cancer invasion and metastasis to brain

Abstract

BackgroundThe 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 (BKCa) 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 BKCa channels in breast cancer metastasis and invasion.MethodsWe 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 BKCa 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 BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX).ResultsThe 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 BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1.ConclusionDetermining the relative abundance of BKCa 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.

Genome-Wide Microarray Expression and Genomic Alterations by Array-CGH Analysis in Neuroblastoma Stem-Like Cells

“…Evidence is particularly extensive for Ca 2+ and K + channels [93] and Romania et al already described their importance in neuroblastoma [94]. In our analysis, several genes coding for Ca 2+ and K + channels were altered in CSC-like subpopulation like KCNMA1 , previously described in prostate cancer [95] and in breast cancer [96], [97], and CACN1AG also altered in gastric cancers, colorectal cancers and acute myeloid leukemia (AML) [98]. Several reports propose that ion transporters have clinical potential not only as therapeutical targets but also as prognosis markers or to improve actual treatments [99]–[103], as blocking channel activity seems to impair the growth of some tumors, including neuroblastoma [99], [104].…”

BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK

“…Abdallah Mound et al recently found that ATP induced cell proliferation could be effectively blocked in MCF-7 cells by downregulation of BKCa [10]. Another study showed that downregulation of BKCa significantly reduced invasion and transendothelial migration of breast cancer cells [13]. In melanoma, BKCa encoding gene KCNMA1 was found to be the target of miRNA-211.…”

A BK (Slo1) channel journey from molecule to physiology

“…211,212 In this section we will briefly discuss some of these findings that link BK channels with the diseases in which they play a major role.…”

“…3C). 212 Amplifications of the BK channel gene have also been observed in many types of prostate cancers. 243 The study of BK channels in prostate cancer has shown that BK channels open at resting potentials and low intracellular Ca 2+ , 244 thus paving the way to find γ subunits.…”