Role of KCNMA1 in Breast Cancer

Abstract

KCNMA1 encodes the α-subunit of the large conductance, voltage and Ca2+-activated (BK) potassium channel and has been reported as a target gene of genomic amplification at 10q22 in prostate cancer. To investigate the prevalence of the amplification in other human cancers, the copy number of KCNMA1 was analyzed by fluorescence-in-situ-hybridization (FISH) in 2,445 tumors across 118 different tumor types. Amplification of KCNMA1 was restricted to a small but distinct fraction of breast, ovarian and endometrial cancer with the highest prevalence in invasive ductal breast cancers and serous carcinoma of ovary and endometrium (3–7%). We performed an extensive analysis on breast cancer tissue microarrays (TMA) of 1,200 tumors linked to prognosis. KCNMA1 amplification was significantly associated with high tumor stage, high grade, high tumor cell proliferation, and poor prognosis. Immunofluorescence revealed moderate or strong KCNMA1 protein expression in 8 out of 9 human breast cancers and in the breast cancer cell line MFM223. KCNMA1-function in breast cancer cell lines was confirmed by whole-cell patch clamp recordings and proliferation assays, using siRNA-knockdown, BK channel activators such as 17ß-estradiol and the BK-channel blocker paxilline. Our findings revealed that enhanced expression of KCNMA1 correlates with and contributes to high proliferation rate and malignancy of breast cancer.

Sp1 transcription factor: A long-standing target in cancer chemotherapy

“…A superior effect is observed on KCNMA1 (Vizcaíno, et al, 2014), a gene associated with high cancer cell proliferation (Oeggerli, et al, 2012). A direct effect is also observed on XIAP, in keeping with that the parental analog mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP through Sp1 sites in its promoter (Lee, et al, 2006).…”

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].…”

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

“…For example, nuclearmtDNA fusion in PD11372a occurred in the fifth intron of the KCNMA1 gene, a potassium channel frequently amplified in prostate and breast cancers (Oeggerli et al 2012). However, we do not find obvious enrichment of the nuclear-mtDNA fusion breakpoints near human nuclear genes.…”