Differentiation of mammary gland as a mechanism to reduce breast cancer risk.

Abstract

Pregnancy, mammary epithelial differentiation, and breast cancer risk Our understanding of the proposed protective role of mammary epithelial differentiation against breast cancer is based mainly on the important work by Irma and Jose Russo (1–3). The Russos have shown that terminal end buds (TEBs) in a rat mammary gland are the structures that give rise to malignant mammary tumors on exposure to chemical carcinogens, particularly to 7,12-dimethylbenz[a]anthracene, a polycyclic aromatic hydrocarbon. Breast cancers in women originate from a corresponding structure called the terminal ductal lobular unit (TDLU) or Lobule type 1 (Lob 1) (4). TEBs play a central role in mammary gland development in rats. The mammary fat pad is initially formed during the fetal period, and it contains limited stroma and a rudimentary epithelial tree. The epithelium is quiescent until about 3 weeks of postnatal age, when large club-shaped TEBs appear. They are the most actively growing terminal ductal structures and are believed to contain a pluripotent stem cell population that potentially gives rise to breast cancer (3,5,6). TEBs lead the growth of the epithelial ducts through the fat pad and eventually regress to terminal ducts or differentiate to alveolar buds and further to lobules when the mammary fat pad is filled with a highly branched ductal tree. These alveolar structures do not give rise to malignant tumors. The work by the Russos and others (7,8) has shown that a key developmental event, pregnancy, as well as exposures that mimic the hormonal environment of pregnancy induce differentiation of the TEB/ TDLU and dramatically reduce the risk of breast cancer. The idea that differentiation explains the protective effects of pregnancy has been questioned by several investigators (9). Arguing against this idea are findings that induction of differentiation by placental lactogen or the dopamine receptor inhibitor perphenazine (PPZ) does not reduce breast cancer risk in animal models. An alternative hypothesis has been proposed by Siverman et al. (10); according to his ‘‘cell fate hypothesis,’’ pregnancy hormones induce a molecular switch in mammary stem cells that leads to changes in cell proliferation and response to DNA damage. The molecular changes then inhibit cell proliferation in response to subsequent exposure to hormones or carcinogens (10,11).