PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.
After lactation, weaning causes mammary epithelial cell (MEC) apoptosis. MECs express the plasma membrane calcium-ATPase 2 (PMCA2), which transports calcium across the apical surface of the cells into milk. Here we show that PMCA2 is down-regulated early in mammary involution associated with changes in MEC shape. We demonstrate that loss of PMCA2 expression raises intracellular calcium levels and sensitizes MECs to apoptosis. In contrast, overexpression of PMCA2 in T47D breast cancer cells lowers intracellular calcium and protects them from apoptosis. Finally, we show that high PMCA2 expression in breast cancers is associated with poor outcome. We conclude that loss of PMCA2 expression at weaning triggers apoptosis by causing cellular calcium crisis. PMCA2 overexpression, on the other hand, may play a role in breast cancer progression by conferring resistance to apoptosis.
Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Joshua
J
VanHouten
Catherine
C
Sullivan
Caroline
C
Bazinet
Tom
T
Ryoo
Robert
R
Camp
David L
DL
Rimm
Gina
G
Chung
John
J
Wysolmerski
D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome
D012333:RNA, Messenger; D053499:Plasma Membrane Calcium-Transporting ATPases; C506958:ATP2B2 protein, human; C506959:Atp2b2 protein, mouse