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

Mol Endocrinol. 2002 Sep;16(9):2034-51. doi: 10.1210/me.2002-0073.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Growth Substances / genetics*
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / growth & development*
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Morphogenesis
  • Oligonucleotide Array Sequence Analysis
  • Parity / genetics*
  • Pregnancy
  • Rats
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta3


  • Growth Substances
  • Tgfb3 protein, mouse
  • Tgfb3 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta3