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

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Abstract

The Bcl-2 gene family regulates tissuedevelopment and tissue homeostasis through the interplayof survival and death factors. Family members arecharacterized as either pro-apoptotic or anti-apoptotic, depending on cellular context. In addition toits anti-apoptotic effect, Bcl-2 also inhibitsprogression through the cell cycle. Functionalinteractions between family members as well as bindingto other cellular proteins modulate their activities.Mammary gland tissue, similar to many other tissues,expresses a number of different Bcl-2 relativesincluding bclx, bax, bak, bad, bcl-w, bfl-1, bcl-2 aswell as the bcl-2 binding protein Bag-1. Bcl-2 isexpressed in the nonpregnant mammary gland and earlypregnancy. In contrast, expression of bcl-x and baxcontinues through late pregnancy, is down-regulated during lactation, and upregulated with thestart of involution. Bak, bad, bcl-w, and bfl-1 are alsoup-regulated during involution. The specific roles ofindividual gene products are investigated using dominant gain of function and loss of functionmice. Finally, different Bcl-2 family members arecommonly over- or under-expressed in human breastcancers. Bcl-2 expression in human breast cancers hasbeen associated with a good prognosis, whiledecreased Bax expression has been linked to poorclinical outcome. Understanding the role Bcl-2 familymembers play in regulating mammary epithelial cellsurvival is salient to both normal mammary glandphysiology and the development of new therapeuticapproaches to breast cancer.