Modulation of transforming growth factor beta 1 gene expression in the mammary gland by insulin-like growth factor I and octreotide

Transforming growth factor beta 1 (TGF-beta 1) has been shown to exhibit an ti-proliferative activity for mammary gland epithelial cells and for human breast cancer cells. Insulin-like growth factor I (IGF-I), in contrast, is a well-characterized mitogenic and anti-apoptotic factor involved in mammar y gland physiology. In order to examine the hypothesis that IGF-I suppresse s TGF-beta 1 expression in the mammary gland, we studied the effect of vari ous manipulations of the growth hormone - IGF-I axis on TGF-beta 1 mRNA abu ndance. Administration of IGF-I to intact animal suppressed TGF-beta 1 mRNA levels in a dose-dependent manner to similar to 20% of control levels. Adm inistration of the somatostatin analogue octreotide in a manner previously shown to acutely suppress the growth hormone - IGF-I axis increased mammary gland TGF-beta 1 expression similar to 3-fold. Transgenic mice overexpress ing growth hormone expressed TGF-beta 1 in the mammary gland at only simila r to 12% of the level of control animals, while mice IGF-I deficient due to the 'lit' mutation expressed TGF-beta 1 at slightly higher levels than con trol animals. The large differences in TGF-beta 1 expression between contro l and GH-transgenic animals were correlated with major differences in archi tecture of the mammary gland, while the appearance of mammary glands of nor mal and 'lit' animals was similar. These data document a previously unrecog nized relationship between TGF-beta 1 and IGF-I physiology in the mammary g land, and suggest a novel mechanism by which somatostatin analogues influen ce the proliferative behaviour of breast epithelial cells.