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Development of Tamoxifen-stimulated Growth of MCF-7 Tumors in Athymic Mice after Long-Term Antiestrogen Administration¹

Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792

Long-term tamoxifen (TAM) therapy was examined in athymic mice bearing MCF-7 tumors of different sizes. Six months of TAM treatment caused no increase in tumor size (compared to placebo treatment) for animals treated initially following implantation of tumor pieces (approximately 1 mm³) or for animals with 0.2-cm² tumors (growth with 1 month of estrogen treatment). Tumors could be regrown with estradiol treatment in animals treated with either therapy and these tumors contained both estrogen and progesterone receptors. However, more tumors could be restimulated with estradiol following pretreatment with TAM than with placebo. A third group of animals had larger tumors (grown with 7 weeks of estrogen treatment to a 0.6-cm² area) before TAM or placebo treatment. These tumors partially regressed after 4 months of TAM or placebo therapy but began to regrow in both groups until the end of the experiment at 8 months. Tumors that grew in both groups were estrogen receptor positive and when retransplanted into athymic animals could grow with estradiol. However, the tumor that grew during TAM therapy, when retransplanted, could grow successfully only with further TAM treatment. Tumors growing with TAM contained double the estrogen receptor content of the estradiol-stimulated MCF-7 tumors that were not exposed to TAM [390 ± 37 (SE) fmol/mg protein versus 174 ± 14 fmol/mg protein]. These results may represent a form of TAM resistance, i.e., TAM dependence that may occur before hormone independence is exhibited.

¹ This investigation was supported by USPHS Grant P01 CA-20432, awarded by the National Cancer Institute.

² Graduate student supported by the Human Cancer Biology Training Program Grant CA-09471 from the NIH.

³ To whom requests for reprints should be addressed, at Department of Human Oncology, University of Wisconsin Clinical Cancer Center, 600 Highland Avenue, Madison, WI 53792.

Received 3/ 7/88. Revised 6/13/88. Accepted 6/21/88.

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