Activation of Stat5 and induction of a pregnancy-like mammary gland differentiation by eicosapentaenoic and docosapentaenoic omega-3 fatty acids

FEBS J. 2007 Jul;274(13):3351-62. doi: 10.1111/j.1742-4658.2007.05869.x. Epub 2007 Jun 5.

Abstract

The protective effect of early pregnancy against breast cancer can be attributed to the transition from undifferentiated cells in the nulliparous to the differentiated mature cells during pregnancy. Considerable evidence suggests strongly that the n-3 polyunsaturated fatty acid (PUFA) content of adipose breast tissue is inversely associated with an increased risk of breast cancer. Here, we report that there was a decrease in the n-6/n-3 PUFA ratio and a significant increase in concentration of n-3 PUFA docosapentaenoic acid and eicosapentaenoic acid in the pregnant gland. The functional role of n-3 PUFAs on differentiation was supported by the studies in the fat-1 transgenic mouse, which converts endogenous n-6 to n-3 PUFAs. Alternation of the n-6/n-3 ratio in favor of n-3 PUFA, and particularly docosapentaenoic acid, in the mammary gland of fat-1 mouse resulted in development of lobulo-alveolar-like structure and milk protein beta-casein expression, mimicking the differentiated state of the pregnant gland. Docosapentaenoic acid and eicosapentaenoic acid activated the Jak2/Stat5 signaling pathway and induced a functional differentiation with production of beta-casein. Expression of brain type fatty acid binding protein brain type fatty acid binding protein in virgin transgenic mice also resulted in a reduced ratio of n-6/n-3 PUFA, a robust increase in docosapentaenoic acid accumulation, and mammary differentiation. These data indicate a role of mammary derived growth inhibitor related gene for preferential accumulation of n-3 docosapentaenoic acid and eicosapentaenoic acid in the differentiated gland during pregnancy. Thus, alternation of n-6/n-3 fatty acid compositional ratio in favor of n-3 PUFA, and particularly docosapentaenoic acid and eicosapentaenoic acid, is one of the underlying mechanisms of pregnancy-induced mammary differentiation.

Publication types

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

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Eicosapentaenoic Acid / metabolism
  • Fatty Acid Binding Protein 3
  • Fatty Acid-Binding Proteins / genetics*
  • Fatty Acids, Omega-3 / metabolism
  • Fatty Acids, Omega-6 / metabolism
  • Fatty Acids, Unsaturated / metabolism*
  • Female
  • Mammary Glands, Animal / metabolism*
  • Mammary Neoplasms, Animal / metabolism*
  • Mice
  • Mice, Transgenic
  • Pregnancy
  • Pregnancy, Animal*

Substances

  • Fabp3 protein, mouse
  • Fatty Acid Binding Protein 3
  • Fatty Acid-Binding Proteins
  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • Fatty Acids, Unsaturated
  • Eicosapentaenoic Acid
  • docosapentaenoic acid