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The Septin 9 (MSF) Gene Is Amplified and Overexpressed in Mouse Mammary Gland Adenocarcinomas and Human Breast Cancer Cell Lines¹

Genetics Branch [C. M., T. Re., Z. W., T. Ri.], Laboratory of Population Genetics [M-S. L., K. H., L. L.], Laboratory of Tumor Immunology and Biology [W. L.], Center for Cancer Research, National Cancer Institute, and Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases [B. H.], NIH, Bethesda, Maryland 20892

The expression of polyomavirus middle T antigen under the control of the mouse mammary tumor virus promoter in transgenic mice results in the induction of aggressive mammary gland adenocarcinomas at an early age. We screened 26 tumors for chromosomal aneuploidies using SKY and CGH. In 70% of the tumor samples we could detect high-level copy number gains, which mapped to chromosome band 11E2, a region orthologous to human 17q25.3. We then identified a bacterial artificial chromosome clone that labeled double-minute chromosomes found in the tumor metaphases. This bacterial artificial chromosome clone showed sequence homology to a member of the septin gene family. Real-time PCR analysis revealed a consistently increased expression of septin 9 (Sept9), not only in polyomavirus middle T antigen-induced, but in a wide variety of mouse models of breast cancer. Six of 9 human tumor cell lines also revealed elevated expression levels of Sept9. The family of septin genes is involved in a plethora of cellular processes, including cytokinesis in yeast and vesicle transport, and possesses GTPase activity. We identified down-regulation of Thsp1- and Bax-regulated apoptotic response in those tumors with Sept9 overexpression, an effect that could be reversed by inhibiting Sept9 expression using transfection with small interference RNA. Our results now suggest that signaling via members of the septin family plays a novel and common role in breast tumorigenesis.

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