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Persistent Parity-Induced Changes in Growth Factors, TGF-ß3, and Differentiation in the Rodent Mammary Gland

Departments of Cancer Biology, of Cell and Developmental Biology, and of Medicine, Division of Endocrinology, Diabetes and Metabolism, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160

Address all correspondence and requests for reprints to: Lewis A. Chodosh, Department of Cancer Biology, University of Pennsylvania School of Medicine, 612 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160. E-mail: chodosh{at}mail.med.upenn.edu.

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-ß3, 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.

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