title: HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients.
abstract: Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cell-cycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target.
authors: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors: Vaishali
authors: V
authors: Pannu
authors: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors: Padmashree C G
authors: PC
authors: Rida
authors: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors: Angela
authors: A
authors: Ogden
authors: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors: Ravi Chakra
authors: RC
authors: Turaga
authors: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors: Shashikiran
authors: S
authors: Donthamsetty
authors: Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, USA.
authors: Nathan J
authors: NJ
authors: Bowen
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors: Katie
authors: K
authors: Rudd
authors: Clinical Pathology & Anatomic Pathology, West Georgia Hospitals, LaGrange, GA, USA.
authors: Meenakshi V
authors: MV
authors: Gupta
authors: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Michelle D
authors: MD
authors: Reid
authors: Department of Gynecologic Oncology, Northside Hospital Cancer Institute, Atlanta, GA, USA.
authors: Guilherme
authors: G
authors: Cantuaria
authors: Department of Medical Sciences, Indiana University, Bloomington, IN, USA.
authors: Claire E
authors: CE
authors: Walczak
authors: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors: Ritu
authors: R
authors: Aneja
mesh_terms: D000782:Aneuploidy; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016547:Kinesins / Q000096:biosynthesis*; D008870:Microtubules / Q000378:metabolism; D060787:Neoplasm Grading; D000077022:Survivin; D014162:Transfection; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; C486566:KIFC1 protein, human; D000077022:Survivin; D016547:Kinesins
keywords: HSET; cell-cycle kinetics; centrosome clustering; microtubule motor; tumor progression