Breast Cancer Research and Treatment 24: 227-239, 1993. © 1993 KluwerAcademic Publishers. Printed in the Netherlands. Hormone resistance, invasiveness, and metastatic potential in breast cancer Robert Clarke, PhD 1'2, Erik W.Thompson, PhD 1'3, Fabio Leonessa, MD 1, Jeremy Lippman MS 1, Michael McGarvey MS I, Thomas L. Frandsen BS 1"4 and Nils Bri.inner, MD ~'4 1 Vincent T. Lombardi Cancer Research Center, 2Department of Physiology & Biophysics, and 3Department of Anatomy & Cell Biology, Georgetown University Medical School, 3800 Reservoir Road NW, Washington, DC 20007, U.S.A.; 4Current Address: Finsen Laboratory, Strandboutevarden 49, 2100 Copenhagen, Denmark. Key words': antiestrogen resistance, clonal selection, epigenetic changes, hormone dependence, malignant progression, metastatic potential, selective pressure Summary Critical phenotypic changes that occur during the progression of breast cancer include the loss of hormone- dependence, acquired resistance to systemic therapies, and increased metastatic potential. We have isolated a series of MCF-7 human breast cancer variants which exhibit hormone-independent growth, antiestrogen resistance, and increased metastatic potential. Analysis of the phenotypes of these variants strongly suggests that changes in the expression of specific genes may be critical to the generation of phenotypic diversity in the process of malignant progression in breast cancer. Epigenetic changes may contribute significantly to the generation of these phenotypic changes observed during breast cancer progression. Many of the characteristics of the progressed phenotypes appear to have arisen in response to appropriate selective pressures (growth in ovariectomized nude mice; growth in the presence of antiestrogens). These observations are consistent with the concept of clonal selection and expansion in the process of malignant progression. Introduction Primary breast carcinomas appear to arise from the epithelial cells of the glandular epithelium, presenting as either intraductal or intralobular lesions. Invasive tumors spread radially by in- filtrating through tissue spaces, and can invade both lymphatic and blood vessels, Many breast tumors produce a high incidence of distant meta- stases, particularly in soft tissues, lungs, liver, bones, and adrenals. The curative potential of current therapies is restricted both by the dis- seminated nature of the disease, and by the pro- gression of the overwhelming majority of tumors to a phenotype characterized by resistance to both cytotoxic drugs and hormonal therapies. We shall discuss recent experimental data relating to anti- estrogen responsiveness, increased metastatic potential, and possible interactions between these phenotypic changes. A significant advantage of antiestrogen therapy (e.g. tamoxifen) is the low incidence of dose Address for offprints: RobertClarke, PhD, Room S 128A VincentT. LombardiCancerResearchCenter,GeorgetownUniversity Medical School, 3800 ReservoirRoad NW, Washington,DC 20007, USA. Telephone (202) 687-3755; Telefax (202) 687-6402.