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MCT-1 Oncogene Contributes to Increased In vivo Tumorigenicity of MCF7 Cells by Promotion of Angiogenesis and Inhibition of Apoptosis

¹ Department of Orthopaedic Surgery and ² Robert H. Lurie Comprehensive Cancer Center; ³ Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; ⁴ Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ⁵ University of Maryland Greenebaum Cancer Center, Baltimore, Maryland

Requests for reprints: Anait S. Levenson, Department of Orthopaedic Surgery, Feinberg School of Medicine, Northwestern University, 645 North Michigan Avenue, S 910, Chicago, IL 60611. Phone: 312-503-3670; Fax: 312-908-8479; E-mail: a-levenson{at}northwestern.edu or Ronald B. Gartenhaus, The University of Maryland Marlene and Stewart Greenebaum Cancer Center, 9-011 BRB, 655 West Baltimore Street, Baltimore, MD 21201. Phone: 410-328-3691; Fax: 410-328-6559; E-mail: rgartenhaus{at}som.umaryland.edu.

Overexpression of a novel oncogene MCT-1 (multiple copies in a T cell malignancy) causes malignant transformation of murine fibroblasts. To establish its role in the pathogenesis of breast cancer in humans, we generated stable transfectants of MCF7 breast cancer cells negative for endogenous MCT-1 (MCF7-MCT-1). Overexpression of MCT-1 in these cells resulted in a slight elevation of estrogen receptor-, and higher rates of DNA synthesis and growth in response to estradiol compared with the empty vector control (MCF7-EV). The pure antiestrogen fulvestrant inhibited the estradiol-stimulated proliferation of MCF7-MCT-1 cells. The MCF7-MCT-1 clones showed increased invasiveness in the presence of 50% serum compared with the MCF7-EV. In a tumor xenograft model, MCT-1–overexpressing cells showed higher take rates and formed significantly larger tumors than MCF7-EV controls. When we examined angiogenic phenotype and molecular mediators of angiogenesis in MCF7-MCT-1 tumors in vivo, we found greater microvascular density and lower apoptosis in the MCF7-MCT-1 tumors compared with MCF7-EV controls accompanied by a dramatic decline in the levels of angiogenesis inhibitor, thrombospondin-1 (TSP1). In vitro, blocking TSP1 in the medium conditioned by MCT-1–negative cells restored its angiogenic potential to that of the MCF7-MCT-1 cells. Conversely, despite an increase in mRNA encoding vascular endothelial growth factor upon MCT-1 overexpression, vascular endothelial growth factor protein levels have not been notably altered. Taken together, our results suggest that MCT-1 may contribute to the pathogenesis and progression of human breast cancer via at least two routes: promotion of angiogenesis through the decline of TSP1 and inhibition of apoptosis.

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