Parity-induced alteration in proliferation, differentiation, and steroid hormone receptor profiles in the rat mammary gland

L KASS; M DURANDO; JG RAMOS; J VARAYOUD; HA RODRÍGUEZ; EH LUQUE; M MUÑOZ-DE-TORO

Boston, MA, USA

Workshop; Gordon Conference in Mammary Gland Biology; 2003

Gordon Research Committe

Parity results in multiple changes within the mammary gland (MG), including persistent increased differentiation and decreased proliferation. In this study we investigated whether parity-related alterations in MG proliferation and differentiation could be associated with changes in steroid hormone receptor profiles. In addition, progesterone signaling through Wnt4 was examined. Mammary glands were removed on day 9 of either first (nulliparous) or third (multiparous) pregnancy. Alterations in all MG tissue compartments were analyzed, as where the role of subsequent lactations. Bromodeoxyuridine (BrdU) incorporation, a-lactalbumin expression, ER (a and b), PR, and other cellular biomarkers were quantified in the MG by immunohistochemistry. Wnt4, ERb1 and ERb2 mRNA isoforms were also evaluated by RT-PCR analysis. In comparison to nulliparous rats, multiparous animals exhibited decreased luminal cell proliferation and PR levels, whereas a-lactalbumin, ERa and ERb expression were increased. Noticeably, not only was total ERb mRNA increased in multiparous rats, the ERb2 isoform was also expressed in these animals.  While parity induced a decrease in proliferative activity in myoepithelial cells, subsequent lactations lead to an increased state of differentiation. Stromal cells did not express PR and exhibited a minimal rate of BrdU incorporation in all groups. In agreement with results obtained in luminal epithelium, levels of ERa and ERb protein were higher in the intralobular stroma of multiparous than nulliparous animals. Our results showed that the lower proliferative activity and higher differentiation state of the multiparous MG are associated with both a decreased PR expression and increased ERa and ERb expression. Reduced PR levels could be associated with the lower proliferative capacity of the MG in multiparous animals; however, it appears this decrease in PR expression is not associated with a reduction in Wnt4 mRNA expression. Instead, results suggest that the decreased proliferative activity and PR expression observed in multiparous animals may be associated with overexpression of ERb and/or the presence of the ERb2 isoform that could antagonize the effects of ERa.