VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.
VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Meghana
M
Rao
Wenqiang
W
Song
Aixiang
A
Jiang
Yu
Y
Shyr
Sima
S
Lev
David
D
Greenstein
Dana
D
Brantley-Sieders
Jin
J
Chen
D000704:Analysis of Variance; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D046228:Microarray Analysis; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D018874:Spheroids, Cellular / Q000166:cytology; D016019:Survival Analysis; D033921:Vesicular Transport Proteins / Q000378:metabolism*
C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D051058:Oncogene Protein v-akt