Carcinogenesis, Vol. 20, No. 4, 677-684,
April 1999
© 1999 Oxford University Press
Induction of mammary carcinomas by N-methyl-N-nitrosourea in ovariectomized rats treated with epidermal growth factor
Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 and
1 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612-7231, USA
The importance of epidermal growth factor (EGF) in both normal and malignant mammary gland development are presented in these studies. Initial findings demonstrated that in the absence of ovarian hormones, EGF had a significant proliferative effect on mammary epithelial cells. To determine whether mammary epithelial cells grown with EGF, in the absence of ovarian hormones, could be transformed by N-methyl-N-nitrosourea (MNU), female ovariectomized Lewis rats were implanted with pellets containing EGF for 1 week and then treated with MNU for initiation. Two days after MNU treatment, ovaries were implanted and EGF pellets were removed from all ovariectomized groups in order to promote carcinogenesis. The mammary carcinoma incidence of the EGF-stimulated group (90%) was not significantly different from the intact group (100%). The mammary cancer morphology of EGF-treated carcinomas was either ductal carcinoma or cribriform adenocarcinoma, whereas intact animals developed mainly papillary and occasional cribriform carcinomas. Fifty-eight percent of the carcinomas from the EGF group were ovarian hormone-independent compared with 10% of carcinomas from the intact group. These results demonstrate that EGF-induced proliferation during initiation with MNU was sufficient to induce the transformation of mammary carcinomas in the absence of ovarian hormones. The hormonal dependency of these EGF-induced carcinomas were different compared with MNU-initiated mammary carcinomas in intact rats.
Abbreviations: BrdU, 5-bromo-2-deoxyuridine; DAB, 3,3'-diaminobenzidine tetrahydrochloride; EGF, epidermal growth factor; ER, estrogen receptor; MECs, mammary epithelial cells; MNU, N-methyl-N-nitrosourea; OHDCs, ovarian hormone-dependent cancers; OHICs, ovarian hormone-independent cancers; PBS, phosphate-buffered saline; PR, progesterone receptor; TGF-
, transforming growth factor .
2 To whom correspondence should be addressed Email: nandilab{at}lsa.berkeley.edu
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