Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo.
Insulin-like growth factor-1 (IGF-1) stimulates proliferation, regulates tissue development, protects against apoptosis, and promotes the malignant phenotype in the breast and other organs. Some epidemiological studies have linked high circulating levels of IGF-1 with an increased risk of breast cancer. To study the role of IGF-1 in mammary tumorigenesis in vivo, we used transgenic mice in which overexpression of IGF-1 is under the control of the bovine keratin 5 (BK5) promoter and is directed to either the myoepithelial or basal cells in a variety of organs, including the mammary gland. This model closely recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 seen in women. Histologically, mammary glands from transgenic mice were hyperplastic and highly vascularized. Mammary glands from prepubertal transgenic mice had significantly increased ductal proliferation compared with wild-type tissues, although this difference was not maintained after puberty. Transgenic mice also had increased susceptibility to mammary carcinogenesis, and 74% of the BK5.IGF-1 mice treated with 7,12-dimethylbenz[a]anthracene (20 microg/day) developed mammary tumors compared with 29% of the wild-type mice. Interestingly, 31% of the vehicle-treated BK5.IGF-1 animals, but none of the wild-type animals, spontaneously developed mammary cancer. The mammary tumors were moderately differentiated adenocarcinomas that expressed functional, nuclear estrogen receptor at both the protein and mRNA levels. These data support the hypothesis that tissue overexpression of IGF-1 stimulates mammary tumorigenesis.
de Ostrovich
Krisztina Kovács
KK
University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.
Lambertz
Isabel
I
Colby
Jennifer K L
JK
Tian
Jie
J
Rundhaug
Joyce E
JE
Johnston
Dennis
D
Conti
Claudio J
CJ
DiGiovanni
John
J
Fuchs-Young
Robin
R
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D019938:Cyclin D1 / Q000096:biosynthesis; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D053555:Keratin-5 / Q000096:biosynthesis; D053533:Keratin-8 / Q000096:biosynthesis; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019899:Paracrine Communication / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D053555:Keratin-5; D053533:Keratin-8; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I