Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland.
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.
Departments 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.
Celina M
CM
D'Cruz
Susan E
SE
Moody
Stephen R
SR
Master
Jennifer L
JL
Hartman
Elizabeth A
EA
Keiper
Marcin B
MB
Imielinski
James D
JD
Cox
James Y
JY
Wang
Seung I
SI
Ha
Blaine A
BA
Keister
Lewis A
LA
Chodosh
D000818:Animals; D002454:Cell Differentiation; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006133:Growth Substances / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis; D020411:Oligonucleotide Array Sequence Analysis; D010298:Parity / Q000235:genetics*; D011247:Pregnancy; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053782:Transforming Growth Factor beta3
D006133:Growth Substances; C509045:Tgfb3 protein, mouse; C509046:Tgfb3 protein, rat; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3