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.
D'Cruz
Celina M
CM
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.
Moody
Susan E
SE
Master
Stephen R
SR
Hartman
Jennifer L
JL
Keiper
Elizabeth A
EA
Imielinski
Marcin B
MB
Cox
James D
JD
Wang
James Y
JY
Ha
Seung I
SI
Keister
Blaine A
BA
Chodosh
Lewis A
LA
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