CONICET | Buscador de Institutos y Recursos Humanos

Introduction:Parity results in multiple changes within the mammary gland; such as higher milk protein and fat content in ewes, and lower proliferation index in rodents. Moreover, in terms of hormone responsiveness in rodent mammary explants, the epithelium from parous females is different from that in nulliparous animals. Objective: In the present study, parity-associated changes in proliferation, differentiation, estrogen-a (ERa) and progesterone (PR) receptorsexpression in the mammary gland of pregnant rats were investigated. The influence of lactation was also evaluated. Methods: Proliferation and differentiation markers were evaluated in the rat mammary gland of a) nulliparous (primigravid animals with eight or more implantation sites), b) multiparous non-lactating (rats that underwent two successful pregnancies but did not nurse their pups ever), and c) multiparous lactating animals (animals that underwent two successful pregnancies and complete periods of lactation). Mammary glands were obtained on day 9 of first or third pregnancy. Bromodeoxyuridine (BrdU) incorporation, ERa and PR receptors, and a-lactalbumin expression were evaluated by immunohistochemistry. Myoepithelial cells were identified using antiserum against a-smooth muscle actin (a-SMA) and p63. The expression of the different markers was assessed in the lobuloalveolar structure (distinguishing between luminal, myoepithelial and intralobular stromal cells), and in the interlobular stroma (fat pad). To evaluate myoepithelial differentiation, the proportion of the alveolar perimeter occupied by the cytoplasmic projections of myoepithelial cells (a-SMA positive), was measured by image analysis and the results expressed as lineal density. Results: In multiparous rats, cell proliferation and PR expression in luminal cells were lower whereas a-lactalbumin and ERa expression were higher than in nulliparous animals. The myoepithelium did not express PR in any group and showed low proliferation index in parous rats. Lactation increased myoepithelial differentiation, while neither the number of myoepithelial cells nor ERa expression in these cells was affected in any of the groups studied. The predominant stromal cell types (fibroblasts and adipocytes) did not express PR and showed a minimal rate of BrdU incorporation in all groups. In agreement with results in luminal epithelium, ERa expression was higher in the intralobular stroma of multiparous than nulliparous animals. Discussion: This study shows that the low proliferative activity of epithelial cells and the high expression of both, a-lactalbumin and ERa, observed in multiparous rats (with or without lactation) when compared to nulliparous animals are associated with a decrease in PR expression. Moreover, the enhanced expression of a-lactalbumin and ERa in multiparous animals is indicative of a different state of differentiation of the luminal compartment. During lactation PR expression is low even thought ERa is high. Since ERa in the mammary epithelium induces PR, a high co-localization of ERa and ERb suggest that the ERb isoform antagonize this effect of ERa. Ongoing studies that evaluate ERb in our model would confirm whether the inhibitory effects of ERb?n explain our results in multiparous animals with regard to PR expression. The regulation of mammary development by progesterone occurs through a paracrine mechanism in which PR positive cells are capable of directing proliferation and/or differentiation of neighboring receptor negative cells. In multiparous rats, the epithelial cells show a lower proliferation index and a different state of differentiation associated with a low PR expression. Therefore, progesterone acting through its receptor is likely to play a role in proliferative activity modulation and/or differentiation of the mammary gland during gestation that may explain some of the persistent parity associated changes in this organ.

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