Intermediate Molecular Biomarkers for the Protective Effect of Pregnancy Against Breast Cancer

Abstract

Abstract : Epidemiological studies have consistently shown an early full-term pregnancy is protective against breast cancer. We hypothesize that the hormonal milieu that is present during pregnancy results in persistent changes in the pattern of gene expression in the mammary gland leading to permanent changes in cell fate that determine the subsequent proliferative response of the gland. To investigate this hypothesis, we have used suppression subtractive hybridization (SSH) to identify genes that are persistently up-regulated in the glands of estrogen and progesterone-treated Wistar-Furth rats 28 days subsequent to steroid hormone treatment compared to age-matched virgins. Using this approach, a number of genes displaying persistent altered expression in response to prior treatment with estrogen and progesterone were identified. Two markers have been characterized in greater detail - RbAp46, and a novel gene that specifies a non-coding RNA (designated GB7). Both were persistently up-regulated in the lobules of the regressed gland and required prior treatment with both estrogen and progesterone for maximal persistent expression. RbAp46 has been implicated in a number of complexes involving chromatin remodeling - thus suggesting a mechanism whereby epigenetic factors responsible for persistent changes in gene expression may be related to the determination of cell fate. These results provide the first support on the molecular level for the hypothesis that hormone-induced persistent changes in gene expression are present in the involuted mammary gland and can affect the response of mammary epithelial cells to carcinogenic insults. In addition, we have developed methods for culturing mammary epithelial cells from the rat and transducing them with a retrovial construct expressing a gene of interest (e.g. RbAp46).