Bcl-2 gene family and related proteins in mammary gland involution and breast cancer

The Bcl-2 gene family regulates tissue development and tissue homeostasis t hrough the interplay of survival and death factors. Family members are char acterized as either pro-apoptotic or anti-apoptotic, depending on cellular context. In addition to its anti-apoptotic effect, Bcl-2 also inhibits prog ression through the cell cycle. Functional interactions between family memb ers as well as binding to other cellular proteins modulate their activities . Mammary gland tissue, similar to many other tissues, expresses a number o f different Bcl-2 relatives including bcl-x, bar, bak, bad, bcl-w, bfl-1, b cl-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 b cl-x and bar continues through late pregnancy, is down-regulated during lac tation, and upregulated with the start of involution. Bak, bad, bcl-w, and bfl-1 are also up-regulated during involution. The specific roles of indivi dual gene products are investigated using dominant gain of function and los s of function mice. Finally, different Bcl-2 family members are commonly ov er- or under-expressed in human breast cancers. Bcl-2 expression in human b reast cancers has been associated with a good prognosis, while decreased Ba r expression has been linked to poor clinical outcome. Understanding the ro le 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.