A classic feature of carcinogenesis is aberrant cell cycle regulation but little is known about how abnormal cell division contributes to malignant progression. Human SEPT9 belongs toa highly conserved eukaryotic family of GTP binding septin proteins importantin cell division. In yeast, septins are coupled to cell cycle progression and are critical for normal morphology. Mammalian SEPT9 is requiredfor normal somatic cell division. SEPT9 is highly homologous to Sept9/Sint1,a murineproto-oncogeneinvolvedin T-cell lymphomasthat is overexpressed in murine models of mammary adenocarcinomas. We originally cloned SEPT9 from a region of allelic imbalance in breast cancers and have subsequently demonstrated SEPT9 amplification in breast cancer cells. We have also observed preferential expression of an alternatively spliced variant, SEPT9v1, in breast cancer cells. Stable ectopic expression of SEPT9v1 studied to date in in vitro models resulted in increased growth kinetics, altered cell morphology, increasedfoci formation, increased invasiveness,abnormal cell division, nuclear mis-localization of the protein, and aneuploidy. SEPT9 was also identified as an MIL fusion partner in leukemia cells. Taken together, findings of: (1) an essential role for SEPT9 in cell division; (2) SEPT9 amplification and preferential expression of SEPT9v1 in breast cancer cells; (3) an altered cell phenotype with increased proliferation, invasiveness, foci formation, and aneuploidy when SEPT9v1variant is ectopically expressed; and (4) homology to an oncogenic murine ortholog overexpressedin breast cancer provide compelling support for our hypothesis that increased expression of SEPT9v1, and possibly additional SEPT9 variants, is associated with abnormal cell division and malignant progression in mammary epithelial cells. To test this hypothesis we will: (1) determine if cellular levels of SEPT9v 1 in an archival panel of well-characterized primary and metastatic mammary tumors correlate with poor prognostic clinicopathological variables clinical outcome; (2) analyze in vitro epithelial cell culture and in vivo tumorigenicity models to determine how increased SEPT9v1impacts cell proliferation, growth characteristics, invasiveness, apoptosis, cell morphology, and genomic stability as related to malignant progression; and (3) evaluate how in vivo overexpression of SEPT9v1 impacts normal mammary gland development and malignant potential by constructing and analyzing tissue specific and conditional transgenic mouse models, including crosses to other transgenicmurine modelsof breastcancer. Resultswill provide insights into how increased SEPT9 v1 expression impacts cell division and tumorigenesis in mammary epithelial cells, which may have significant prognostic and/or therapeutic implications.
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