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Mol Endocrinol. 2002 Sep;16(9):2034-51.

Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland.

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  • 1Departments of Cancer Biology, of Cell and Developmental Biology, and of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.

Abstract

Epidemiological studies have repeatedly demonstrated that women who undergo an early first full-term pregnancy have a significantly reduced lifetime risk of breast cancer. Similarly, rodents that have previously undergone a full-term pregnancy are highly resistant to carcinogen-induced breast cancer compared with age-matched nulliparous controls. Little progress has been made, however, toward understanding the biological basis of this phenomenon. We have used DNA microarrays to identify a panel of 38 differentially expressed genes that reproducibly distinguishes, in a blinded manner, between the nulliparous and parous states of the mammary gland in multiple strains of mice and rats. We find that parity results in the persistent down-regulation of multiple genes encoding growth factors, such as amphiregulin, pleiotrophin, and IGF-1, as well as the persistent up-regulation of the growth-inhibitory molecule, TGF-beta3, and several of its transcriptional targets. Our studies further indicate that parity results in a persistent increase in the differentiated state of the mammary gland as well as lifelong changes in the hematopoietic cell types resident within the gland. These findings define a developmental state of the mammary gland that is refractory to carcinogenesis and suggest novel hypotheses for the mechanisms by which parity may modulate breast cancer risk.

PMID:
12198241
[PubMed - indexed for MEDLINE]
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