Persistent changes in gene expression induced by estrogen and progesteronein the rat mammary gland

Epidemiological studies have consistently shown that an early full-term pre gnancy is protective against breast cancer. We hypothesize that the hormona l milieu that is present during pregnancy results in persistent changes in the pattern of gene expression in the mammary gland, leading to permanent c hanges in cell fate that determine the subsequent proliferative response of the gland. To investigate this hypothesis, we have used suppression subtra ctive hybridization to identify genes that are persistently up-regulated in the glands of E-and progesterone (P)-treated Wistar-Furth rats 28 d after steroid hormone treatment compared with age-matched virgins. Using this app roach, a number of genes displaying persistent altered expression in respon se to previous treatment with E and P were identified. Two markers have bee n characterized in greater detail: RbAp46 and a novel gene that specifies a noncoding RNA (designated G.B7). Both were persistently up-regulated in th e lobules of the regressed gland and required previous treatment with both E and P for maximal persistent expression. RbAp46 has been implicated in a number of complexes involving chromatin remodeling, suggesting a mechanism whereby epigenetic factors responsible for persistent changes in gene expre ssion may be related to the determination of cell fate. These results provi de the first support at the molecular level for the hypothesis that hormone -induced persistent changes in gene expression are present in the involuted mammary gland.