Modulation of transforming growth factor β1 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 anti-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 mammary gland physiology. In order to examine the hypothesis that IGF-I suppresses TGF-beta 1 expression in the mammary gland, we studied the effect of various manipulations of the growth hormone - IGF-I axis on TGF-beta 1 mRNA abundance. 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. Administration 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 overexpressing growth hormone expressed TGF-beta 1 in the mammary gland at only similar 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 control animals. The large differences in TGF-beta 1 expression between control and GH-transgenic animals were correlated with major differences in architecture of the mammary gland, while the appearance of mammary glands of normal and 'lit' animals was similar. These data document a previously unrecognized relationship between TGF-beta 1 and IGF-I physiology in the mammary gland, and suggest a novel mechanism by which somatostatin analogues influence the proliferative behaviour of breast epithelial cells.