Suppression of mammary-derived growth inhibitor gene expression by growth hormone and insulin-like growth factor I.
When introduced into MCF-7 breast cancer cells, the mammary-derived growth inhibitor (MDGI) gene causes them to revert to a more normal behavior. MDGI is silenced in several human breast cancer cell lines and in most breast tumors. Antiestrogens (tamoxifen and ICI 182780), which are commonly used in breast cancer treatment, stabilize MDGI mRNA. Insulin-like growth factors (IGFs) are well characterized mitogenic and anti-apoptotic factors involved in mammary gland physiology. We demonstrate that MDGI gene expression was inversely correlated with IGF-II gene expression. In the mammary gland of growth hormone releasing hormone receptor mutant (Ghrhrlit/Ghrhrlit) mice, the MDGI gene was overexpressed. Administration of IGF-I or GH to Ghrhrlit/Ghrhrlit mice suppressed MDGI mRNA levels in a dose-dependent manner. Administration of the somatostatin analogue octreotide to pituitary intact rats in a manner previously shown to acutely suppress the GH/IGF-I axis, up-regulated mammary gland MDGI expression in a dose-dependent fashion. The data document a previously unrecognized role of IGF-I in the regulation of the tumor suppressor gene MDGI, in the mammary gland, and may aid in the design of new physiological approaches to breast cancer prevention and/or treatment.
McGill University Centre for Translational Research in Cancer, Lady Davis Research Institute, Montreal, H3T 1E2 Quebec, Canada.
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D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D013006:Growth Hormone / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000096:biosynthesis / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology
D002273:Carcinogens; D002352:Carrier Proteins; C493408:FABP3 protein, human; C509948:FABP3 protein, rat; C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D012333:RNA, Messenger; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D011994:Recombinant Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor