PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer

Abstract

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. intracellular calcium

Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells

“…A recent study showed that elevated PMCA2 expression in mammary epithelial cells inhibited apoptosis and in human breast cancer cases a high PMCA2 mRNA level was associated with poor clinical prognosis [62]. In breast cancer cell lines PMCA1 and PMCA2 was shown to be expressed at an increased level compared to non-tumorigenic cells [11,12] although, in one study PMCA2 mRNA was not detected by RT-PCR in MCF-7 cells [63].…”

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

“…After weaning, PMCA2 expression rapidly decreases, contributing to the initiation of programmed cell death and mammary gland involution (7,8). PMCA2 is also expressed in breast cancers (8)(9)(10), and high levels of tumor PMCA2 expression predict increased mortality in patients (8).…”

“…PMCA2 (gene symbol Atp2b2) is highly expressed in the apical membrane of mammary epithelial cells only during lactation, where it has been shown to transport calcium into milk (4-6). After weaning, PMCA2 expression rapidly decreases, contributing to the initiation of programmed cell death and mammary gland involution (7,8). PMCA2 is also expressed in breast cancers (8-10), and high levels of tumor PMCA2 expression predict increased mortality in patients (8).…”

“…PMCA2 levels correlate with HER2 in breast tumors (8). To further explore potential interactions between PMCA2 and HER2, we analyzed their expression in a previously reported tissue microarray consisting of 652 breast cancers with a median 9 y of clinical follow-up (8,16).…”

Transcriptomic analysis reveals key regulators of mammogenesis and the pregnancy-lactation cycle

“…The remaining three, which are members of the Casein gene family, are also major proteins during lactation. As for the 7-fold down-regulated gene, Atp2b2, whose structure is similar to those of the SERCA calcium pumps, this function as a calcium transporter that moves calcium across the apical surface of cells into the milk [48,49]. The Lpo gene encodes an oxidoreductase that acts as a natural antibacterial agent in the innate immune system by killing bacteria in milk.…”