HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

Vaishali Pannu, Padmashree C G Rida, Angela Ogden, Ravi Chakra Turaga, Shashikiran Donthamsetty, Nathan J. Bowen, Katie Rudd, Meenakshi V. Gupta, Michelle D. Reid, Guilherme Cantuaria, Claire Walczak, Ritu Aneja

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 cellcycle 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.

Original languageEnglish (US)
Pages (from-to)6076-6091
Number of pages16
JournalOncotarget
Volume6
Issue number8
StatePublished - 2015

Fingerprint

Centrosome
Cluster Analysis
Breast Neoplasms
Neoplasms
Aneuploidy
Kinesin
Survival
Gene Amplification
G2 Phase
Proteasome Endopeptidase Complex
Mitosis
Microtubules
Cell Division
Disease-Free Survival
Cell Survival
Biomarkers
Phenotype
Proteins

Keywords

  • Cell-cycle kinetics
  • Centrosome clustering
  • HSET
  • Microtubule motor
  • Tumor progression

ASJC Scopus subject areas

  • Oncology

Cite this

Pannu, V., Rida, P. C. G., Ogden, A., Turaga, R. C., Donthamsetty, S., Bowen, N. J., ... Aneja, R. (2015). HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients. Oncotarget, 6(8), 6076-6091.

HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients. / Pannu, Vaishali; Rida, Padmashree C G; Ogden, Angela; Turaga, Ravi Chakra; Donthamsetty, Shashikiran; Bowen, Nathan J.; Rudd, Katie; Gupta, Meenakshi V.; Reid, Michelle D.; Cantuaria, Guilherme; Walczak, Claire; Aneja, Ritu.

In: Oncotarget, Vol. 6, No. 8, 2015, p. 6076-6091.

Research output: Contribution to journalArticle

Pannu, V, Rida, PCG, Ogden, A, Turaga, RC, Donthamsetty, S, Bowen, NJ, Rudd, K, Gupta, MV, Reid, MD, Cantuaria, G, Walczak, C & Aneja, R 2015, 'HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients', Oncotarget, vol. 6, no. 8, pp. 6076-6091.
Pannu V, Rida PCG, Ogden A, Turaga RC, Donthamsetty S, Bowen NJ et al. HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients. Oncotarget. 2015;6(8):6076-6091.
Pannu, Vaishali ; Rida, Padmashree C G ; Ogden, Angela ; Turaga, Ravi Chakra ; Donthamsetty, Shashikiran ; Bowen, Nathan J. ; Rudd, Katie ; Gupta, Meenakshi V. ; Reid, Michelle D. ; Cantuaria, Guilherme ; Walczak, Claire ; Aneja, Ritu. / HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients. In: Oncotarget. 2015 ; Vol. 6, No. 8. pp. 6076-6091.
@article{2f2e06dee3cb4739a596fd088cf79d36,
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 cellcycle 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.",
keywords = "Cell-cycle kinetics, Centrosome clustering, HSET, Microtubule motor, Tumor progression",
author = "Vaishali Pannu and Rida, {Padmashree C G} and Angela Ogden and Turaga, {Ravi Chakra} and Shashikiran Donthamsetty and Bowen, {Nathan J.} and Katie Rudd and Gupta, {Meenakshi V.} and Reid, {Michelle D.} and Guilherme Cantuaria and Claire Walczak and Ritu Aneja",
year = "2015",
language = "English (US)",
volume = "6",
pages = "6076--6091",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "8",

}

TY - JOUR

T1 - HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients

AU - Pannu, Vaishali

AU - Rida, Padmashree C G

AU - Ogden, Angela

AU - Turaga, Ravi Chakra

AU - Donthamsetty, Shashikiran

AU - Bowen, Nathan J.

AU - Rudd, Katie

AU - Gupta, Meenakshi V.

AU - Reid, Michelle D.

AU - Cantuaria, Guilherme

AU - Walczak, Claire

AU - Aneja, Ritu

PY - 2015

Y1 - 2015

N2 - 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 cellcycle 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.

AB - 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 cellcycle 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.

KW - Cell-cycle kinetics

KW - Centrosome clustering

KW - HSET

KW - Microtubule motor

KW - Tumor progression

UR - http://www.scopus.com/inward/record.url?scp=84925590330&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925590330&partnerID=8YFLogxK

M3 - Article

C2 - 25788277

AN - SCOPUS:84925590330

VL - 6

SP - 6076

EP - 6091

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 8

ER -