Bcl-2 Gene Family and Related Proteins in Mammary Gland Involution and Breast Cancer

Overview

Journal J Mammary Gland Biol Neoplasia

Date 1999 Jul 30

PMID 10426394

Citations 24

Authors

K Schorr

M Li

S Krajewski

J C Reed

P A Furth

Affiliations

Soon will be listed here.

Abstract

The Bcl-2 gene family regulates tissue development and tissue homeostasis through the interplay of survival and death factors. Family members are characterized as either pro-apoptotic or anti-apoptotic, depending on cellular context. In addition to its anti-apoptotic effect, Bcl-2 also inhibits progression through the cell cycle. Functional interactions between family members as well as binding to other cellular proteins modulate their activities. Mammary gland tissue, similar to many other tissues, expresses a number of different Bcl-2 relatives including bcl-x, bax, bak, bad, bcl-w, bfl-1, bcl-2 as well as the bcl-2 binding protein Bag-1. Bcl-2 is expressed in the nonpregnant mammary gland and early pregnancy. In contrast, expression of bcl-x and bax continues through late pregnancy, is down-regulated during lactation, and upregulated with the start of involution. Bak, bad, bcl-w, and bfl-1 are also up-regulated during involution. The specific roles of individual gene products are investigated using dominant gain of function and loss of function mice. Finally, different Bcl-2 family members are commonly over- or under-expressed in human breast cancers. Bcl-2 expression in human breast cancers has been associated with a good prognosis, while decreased Bax expression has been linked to poor clinical outcome. Understanding the role Bcl-2 family members play in regulating mammary epithelial cell survival is salient to both normal mammary gland physiology and the development of new therapeutic approaches to breast cancer.

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References

Yang E, Zha J, Jockel J, Boise L, Thompson C, Korsmeyer S . Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995; 80(2):285-91. DOI: 10.1016/0092-8674(95)90411-5. View

Dubois-Dauphin M, Frankowski H, Tsujimoto Y, Huarte J, Martinou J . Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death. Proc Natl Acad Sci U S A. 1994; 91(8):3309-13. PMC: 43566. DOI: 10.1073/pnas.91.8.3309. View

Yang J, Liu X, Bhalla K, Kim C, Ibrado A, Cai J . Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997; 275(5303):1129-32. DOI: 10.1126/science.275.5303.1129. View

Chao D, Korsmeyer S . BCL-2 family: regulators of cell death. Annu Rev Immunol. 1998; 16:395-419. DOI: 10.1146/annurev.immunol.16.1.395. View

Borner C . Diminished cell proliferation associated with the death-protective activity of Bcl-2. J Biol Chem. 1996; 271(22):12695-8. DOI: 10.1074/jbc.271.22.12695. View

Liu X, Kim C, Yang J, Jemmerson R, Wang X . Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996; 86(1):147-57. DOI: 10.1016/s0092-8674(00)80085-9. View

Zapata J, Krajewska M, Krajewski S, Huang R, Takayama S, Wang H . Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumors. Breast Cancer Res Treat. 1998; 47(2):129-40. DOI: 10.1023/a:1005940832123. View

Chittenden T, Flemington C, Houghton A, Ebb R, Gallo G, Elangovan B . A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 1995; 14(22):5589-96. PMC: 394673. DOI: 10.1002/j.1460-2075.1995.tb00246.x. View

Huang D, OReilly L, Strasser A, Cory S . The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J. 1997; 16(15):4628-38. PMC: 1170089. DOI: 10.1093/emboj/16.15.4628. View

10.

Hockenbery D, Zutter M, Hickey W, Nahm M, Korsmeyer S . BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A. 1991; 88(16):6961-5. PMC: 52213. DOI: 10.1073/pnas.88.16.6961. View

11.

Nakayama K, Negishi I, Kuida K, Shinkai Y, Louie M, Fields L . Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice. Science. 1993; 261(5128):1584-8. DOI: 10.1126/science.8372353. View

12.

Takayama S, Bimston D, Matsuzawa S, Freeman B, Aime-Sempe C, Xie Z . BAG-1 modulates the chaperone activity of Hsp70/Hsc70. EMBO J. 1997; 16(16):4887-96. PMC: 1170124. DOI: 10.1093/emboj/16.16.4887. View

13.

Grillot D, Merino R, PENA J, Fanslow W, Finkelman F, Thompson C . bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice. J Exp Med. 1996; 183(2):381-91. PMC: 2192442. DOI: 10.1084/jem.183.2.381. View

14.

Rosse T, Olivier R, Monney L, Rager M, Conus S, Fellay I . Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature. 1998; 391(6666):496-9. DOI: 10.1038/35160. View

15.

Krajewski S, Krajewska M, Shabaik A, Miyashita T, Wang H, Reed J . Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol. 1994; 145(6):1323-36. PMC: 1887502. View

16.

Takayama S, Krajewski S, Krajewska M, Kitada S, Zapata J, Kochel K . Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines. Cancer Res. 1998; 58(14):3116-31. View

17.

El-Deiry W, Harper J, OConnor P, Velculescu V, Canman C, Jackman J . WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994; 54(5):1169-74. View

18.

Ross A, Waymire K, Moss J, Parlow A, Skinner M, Russell L . Testicular degeneration in Bclw-deficient mice. Nat Genet. 1998; 18(3):251-6. DOI: 10.1038/ng0398-251. View

19.

Krajewski S, Hugger A, Krajewska M, Reed J, Mai J . Developmental expression patterns of Bcl-2, Bcl-x, Bax, and Bak in teeth. Cell Death Differ. 1999; 5(5):408-15. DOI: 10.1038/sj.cdd.4400360. View

20.

Knudson C, Tung K, Tourtellotte W, Brown G, Korsmeyer S . Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995; 270(5233):96-9. DOI: 10.1126/science.270.5233.96. View