PMCA2 Regulates Apoptosis During Mammary Gland Involution and Predicts Outcome in Breast Cancer

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jun 11

PMID 20534448

Citations 58

Authors

Joshua VanHouten

Catherine Sullivan

Caroline Bazinet

Tom Ryoo

Robert Camp

David L Rimm

Gina Chung

John Wysolmerski

Affiliations

Soon will be listed here.

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.

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References

Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D . Identification of molecular apocrine breast tumours by microarray analysis. Oncogene. 2005; 24(29):4660-71. DOI: 10.1038/sj.onc.1208561. View

Chang J, Wooten E, Tsimelzon A, Hilsenbeck S, Gutierrez M, Elledge R . Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet. 2003; 362(9381):362-9. DOI: 10.1016/S0140-6736(03)14023-8. View

Li M, Liu X, Robinson G, Bar-Peled U, Wagner K, Young W . Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A. 1997; 94(7):3425-30. PMC: 20386. DOI: 10.1073/pnas.94.7.3425. View

Lee W, Monteith G, Roberts-Thomson S . Calcium transport and signaling in the mammary gland: targets for breast cancer. Biochim Biophys Acta. 2006; 1765(2):235-55. DOI: 10.1016/j.bbcan.2005.12.001. View

Gil-Parrado S, Fernandez-Montalvan A, Assfalg-Machleidt I, Popp O, Bestvater F, Holloschi A . Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members. J Biol Chem. 2002; 277(30):27217-26. DOI: 10.1074/jbc.M202945200. View

Watson C . Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res. 2006; 8(2):203. PMC: 1557708. DOI: 10.1186/bcr1401. View

Demaurex N, Distelhorst C . Cell biology. Apoptosis--the calcium connection. Science. 2003; 300(5616):65-7. DOI: 10.1126/science.1083628. View

Chapman R, Lourenco P, Tonner E, Flint D, Selbert S, Takeda K . Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev. 1999; 13(19):2604-16. PMC: 317074. DOI: 10.1101/gad.13.19.2604. View

Quaglino A, Salierno M, Pellegrotti J, Rubinstein N, C Kordon E . Mechanical strain induces involution-associated events in mammary epithelial cells. BMC Cell Biol. 2009; 10:55. PMC: 2721828. DOI: 10.1186/1471-2121-10-55. View

10.

Reinhardt T, Lippolis J, Shull G, Horst R . Null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2 impairs calcium transport into milk. J Biol Chem. 2004; 279(41):42369-73. DOI: 10.1074/jbc.M407788200. View

11.

Matsuda M, Imaoka T, Vomachka A, Gudelsky G, Hou Z, Mistry M . Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev Cell. 2004; 6(2):193-203. DOI: 10.1016/s1534-5807(04)00022-x. View

12.

Clarkson R, Heeley J, Chapman R, Aillet F, Hay R, Wyllie A . NF-kappaB inhibits apoptosis in murine mammary epithelia. J Biol Chem. 2000; 275(17):12737-42. DOI: 10.1074/jbc.275.17.12737. View

13.

Alcaraz J, Xu R, Mori H, Nelson C, Mroue R, Spencer V . Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia. EMBO J. 2008; 27(21):2829-38. PMC: 2569873. DOI: 10.1038/emboj.2008.206. View

14.

Oda A, Wakao H, Fujita H . Calpain is a signal transducer and activator of transcription (STAT) 3 and STAT5 protease. Blood. 2002; 99(5):1850-2. DOI: 10.1182/blood.v99.5.1850. View

15.

Watson C, Neoh K . The Stat family of transcription factors have diverse roles in mammary gland development. Semin Cell Dev Biol. 2008; 19(4):401-6. DOI: 10.1016/j.semcdb.2008.07.021. View

16.

Neville M, McFadden T, Forsyth I . Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia. 2002; 7(1):49-66. DOI: 10.1023/a:1015770423167. View

17.

Baxter F, Neoh K, Tevendale M . The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia. 2007; 12(1):3-13. DOI: 10.1007/s10911-007-9033-9. View

18.

Reinhardt T, Filoteo A, Penniston J, Horst R . Ca(2+)-ATPase protein expression in mammary tissue. Am J Physiol Cell Physiol. 2000; 279(5):C1595-602. DOI: 10.1152/ajpcell.2000.279.5.C1595. View

19.

Santos S, Haslam S, Conrad S . Estrogen and progesterone are critical regulators of Stat5a expression in the mouse mammary gland. Endocrinology. 2007; 149(1):329-38. PMC: 2194608. DOI: 10.1210/en.2007-0594. View

20.

Hendry L, John S . Regulation of STAT signalling by proteolytic processing. Eur J Biochem. 2004; 271(23-24):4613-20. DOI: 10.1111/j.1432-1033.2004.04424.x. View