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Pregnancy-dependent Growth of Mammary Tumors Is Associated with Overexpression of Insulin-like Growth Factor II¹

Lady Davis Research Institute of the Jewish General Hospital and Departments of Oncology and Medicine, McGill University, 3755 Cote Ste Catherine Road, Montreal, Quebec H3T 1E2, Canada

We demonstrate that although IGF-II gene expression is approximately 3-fold higher in 9,10-dimethyl-1,2-benzanthracine (DMBA)-induced rat mammary tumors (MTs) than in nonneoplastic breast tissue, IGF-II mRNA abundance in DMBA-induced MTs is approximately 130-fold higher in pregnant as compared to nonpregnant hosts. This correlated with accelerated tumor growth in pregnant hosts. Immunohistochemical studies of DMBA-induced MTs with an anti-IGF-II antibody showed an intense staining of tumor cells for IGF-II, whereas a very low staining signal was observed for normal epithelial cells in the lobules. A similar immunostaining pattern was observed in three of three human ductal cancers and adjacent normal breast tissue obtained during pregnancy. DMBA-induced MTs expressed high levels of type I receptor for IGFs as determined by Northern blots. In vitro studies confirmed that IGF-II is a mitogen for neoplastic epithelial cells derived from DMBA-induced MTs. These results demonstrate that hormonal changes associated with pregnancy accelerate breast cancer cell proliferation in the DMBA-induced MT model and suggest that this acceleration is mediated by up-regulation of IGF-II expression within neoplasms.

¹ This work was supported by grants from the Canadian Breast Cancer Foundation (Grant 6032) to H. H., the National Institute of Canada to M. P., and the Jewish General Hospital Internal Awards Committee to L. A.

² To whom requests for reprints should be addressed. Phone: (514) 340-8260, ext. 3668; Fax: (514) 340-7502.

Received 6/ 3/96. Accepted 7/ 2/96.

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