Figure 1

Unified model for parity-specific changes in the mammary gland. (a) Summary of reported parity-dependent changes in the mammary gland. Pregnancy induces multiple changes in the mammary epithelial cells, including nuclear accumulation of p53 and induction of whey acidic protein (WAP)-Cre expression (and subsequently β-galactosidase expression, indicated by blue cells) in WAP-Cre/Rosa-LacZ mice, and alteration in gene activity perhaps leading to changes in cell fate. During involution, a large component of the epithelium is eliminated through programmed cell death; however, a specific subpopulation is able to circumvent this process. The involuted mammary gland is characterized by persistent changes in gene expression, nuclear localization of p53, and an altered proliferative capacity in response to carcinogen. (b) Potential mechanism for the parity-specific changes in cell fate: Pregnancy invokes epigenetic changes affecting cell fate in the parous mammary gland. Epigenetic changes may be induced by a number of mechanisms, including chromatin remodeling, DNA methylation/demethylation, and histone modification, and as a result of de novo chromatin assembly. RbAp46 is a component of a number of complexes responsible for these processes, including the NuRD complex [23], which also contains methyl-CpG binding domain proteins (MBD). The common presence of RbAp46 in these complexes might thus provide a mechanism for sequential shuttling between these different functions, and in addition provides a link between DNA methylation and chromatin regulation. Noncoding RNAs have also been implicated in these changes in gene expression, through their association with chromatin remodeling, histone acetylation/deacetylation, and transcription factor complexes, as well as RNA interference [24, 25]. Epigenetic changes can regulate cell fate in a number of ways, for instance by altering gene activity, by providing a signal for survival or proliferation, and by mediating responses to DNA damage. In addition, it is likely that there is continual cross-talk between the epithelium and the stroma, thus providing an additional level of epigenetic regulation in the parous mammary gland. Ac, acetylated histones; M, methylated cytosine; TF, transcription factor.