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Transforming Acidic Coiled Coil 1 Promotes Transformation and Mammary Tumorigenesis

¹ Campbell Family Institute for Breast Cancer Research; Departments of ² Medical Biophysics and ³ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; ⁴ Institute for Biochemistry and Molecular Biology II, Heinrich Heine University, Duesseldorf, Germany; and ⁵ Molecular Oncology Group, McGill University, Montreal, Quebec, Canada

Requests for reprints: Tak W. Mak, Campbell Family Institute for Breast Cancer Research, 620 University Ave, Suite 706, Toronto, Ontario, Canada M5G 2C1. Phone: 416-946-2234; Fax: 416-204-5300; E-mail: tmak{at}uhnres.utoronto.ca.

Transforming acidic coiled coil 1 (TACC1) is a putative oncogene located within a breast cancer amplicon found on human chromosome 8p11. Although TACC1 has been reported to transform fibroblasts, it is also down-regulated in a subset of mammary tumors treated with anthracyclin. Here, we show that ectopic TACC1 overexpression can cooperate with Ras to induce focus formation in murine fibroblast cultures and prevent death caused by overexpression of Pten or a dominant-negative form of protein kinase B (PKB)/Akt. In transgenic mice carrying TACC1 under the control of the mouse mammary tumor virus promoter, TACC1 expression reduced apoptosis during mammary gland involution, increased the penetrance of mammary tumors in a pten^+/– background, and decreased the average age of mammary tumor onset in a mouse model based on a phosphatidylinositol 3'-kinase (PI3K)–decoupled mutant of polyoma middle T. Elevated levels of both phospho-PKB and phospho-extracellular signal-regulated kinase were found in mammary tissue containing the TACC1 transgene. Thus, TACC1 positively regulates the Ras and PI3K pathways, promotes Ras-mediated transformation, and prevents apoptosis induced by PI3K pathway inhibition. TACC1 also cooperates with tumorigenic mutations in the PI3K pathway and thereby plays an oncogenic role in tumor formation in the murine mammary gland.

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