Role of KCNMA1 in breast cancer.
KCNMA1 encodes the α-subunit of the large conductance, voltage and Ca(2+)-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.
Institute of Pathology, University of Basel, Basel, Switzerland. oeggerlim@uhbs.ch
Martin
M
Oeggerli
Yuemin
Y
Tian
Christian
C
Ruiz
Barbara
B
Wijker
Guido
G
Sauter
Ellen
E
Obermann
Uwe
U
Güth
Inti
I
Zlobec
Matthias
M
Sausbier
Karl
K
Kunzelmann
Lukas
L
Bubendorf
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
D047628:Estrogen Receptor alpha; C494841:KCNMA1 protein, human; D019394:Ki-67 Antigen; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D011980:Receptors, Progesterone