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Acquisition of Hormone-independent Growth in MCF-7 Cells Is Accompanied by Increased Expression of Estrogen-regulated Genes but Without Detectable DNA Amplifications¹

Vincent T. Lombardi Cancer Research Center, Georgetown University Medical School, Washington, DC 20007 [N. B., V. B., C. E. F, M. E. L., R. C.], and the Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [A. F.]

³ To whom requests for reprints should be addressed, at Room S128A, Vincent T. Lombardi Cancer Research Center, Georgetown University Medical School, 3800 Reservoir Road NW, Washington, DC 20007.

A hormone-independent but hormone-responsive subpopulation (MCF7/MIII) of the hormone-dependent MCF-7 human breast cancer cell line (R. Clarke et al., Proc. Natl. Acad. Sci. USA 86: 3649–3653, 1989) was further passaged in ovariectomized nude mice and re-established in vitro as the continuous cell line MCF7/LCC1. The lag time to the appearance of proliferating tumors in ovariectomized animals is significantly reduced in MCF7/LCC1 when compared with MCF7/MIII cells. In gel denaturation/renaturation analysis of tumor, genomic DNA does not reveal significant differences in the pattern of detectable DNA amplifications between parent MCF-7 cells and MCF7/LCC1 cells. In the absence of estrogen, steadystate levels of phosphoinositol turnover are similar in both MCF-7 and MCF7/LCC1 cells, but turnover is increased by estrogen only in MCF-7 cells. MCF7/MIII and MCF7/LCC1, but not MCF-7 cells, express a high baseline level of the estrogen-regulated pS2 mRNA. The baseline level of expression of progesterone receptor protein, but not mRNA, is higher in MCF7/LCC1 when compared with either MCF-7 or early passage MCF7/MIII cells. However, while the estrogen receptor is also an estrogen-regulated gene, MCF7/MIII and MCF7/LCC1 cells retain estrogen receptor levels equivalent to the parental MCF-7 cells. These data indicate that progression to hormone independence can occur without major gene amplifications or a high constitutive induction of phosphoinositide metabolism. Thus, DNA amplifications may be acquired during the early initiation and/or promotional events of carcinogenesis. Significantly, acquisition of a hormone-independent but responsive phenotype in human breast cancer is associated with perturbations in the expression of specific estrogen-regulated genes.

¹ This work was supported by USPHS Grants 1-R55-CA51782, 5-R01-CA58022 (R. C.), and 5-U01-CA51908 and Grant 1P30-CA51008 from the National Cancer Institute (M. E. L., R. C.); Research Grant 90BW65 from the American Institute for Cancer Research (R. C.); Fellowships from the Danish Cancer Society and National Cancer Institute/European Organization for Reasearch on Treatment of Cancer Exchange Program (N. B.); and Fondation pour la Recherche Medicale, and L'Association pour la Recherche sur le Cancer (V. B.).

² Current address: Finsen Laboratory, Strandboulevarden 49, 2100 Copenhagen, Denmark.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/ 3/91. Accepted 10/26/92.

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