Role of KCNMA1 gene in breast cancer invasion and metastasis to brain.

Abstract

Abstract Abstract #2043 Background: The prognosis for patients with brain metastasis from breast cancer is extremely poor. A significant number of breast tumor patients despite aggressive therapy develop metastatic disease in brain. The mechanism or the cause of breast cancer metastasis to brain is unknown. Therefore, it is critical to identify prognostic molecular markers of the metastatic process in order to design therapeutic modalities for reducing the occurrence of metastasis. In this study we investigated KCNMA1 gene, which encodes alpha subunit of calcium activated potassium (KCa) channels. Altered KCa channels, are described in a wide variety of tumor cell types and up-regulation of KCa channels was shown to be a novel mechanism for the malignant phenotype of human tumor cells.
 Material and Methods: We performed Global GeneChip exon arrays to study the expression of KCNMA1 gene in metastatic breast cancer in brain and compared it with primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immuno-histochemistry was performed to study the expression and localization of alpha subunit of KCa channel protein in primary and metastatic breast tumor tissues and breast cancer cell lines. We performed Matrigel invasion, transendothelial migration and membrane potential assays in 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 KCa channel inhibition attenuates breast tumor invasion and metastasis to brain.
 Results: The Global GeneChip exon array and RT-PCR showed higher KCNMA1 gene 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 KCa channel activity, leading to greater invasion and trans-endothelial migration, which could be attenuated by blocking the KCNMA1 gene with siRNA and biochemical inhibition with IBTX.
 Discussion: Recent investigations in patients with metastatic lung and breast cancers reported alarming rates of brain metastases. Unraveling the genetic aberrations that drive the metastatic events in these cancer cells offer insights into how to limit or prevent this lethal process. For instance, determining the relative abundance of KCNMA1 gene in breast cancer metastasis to brain and understanding the mechanism of brain metastasis provides a unique opportunity to identify specific genetic markers that could differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This would in turn allow for the appropriate and efficient application of treatments to obtain the greatest benefit while sparing low risk patients for metastasis from the toxic side effects of chemotherapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2043.