High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

Sandro Santagata, Rong Hu, Nancy U. Lin, Marc L. Mendillo, Laura C. Collins, Susan E. Hankinson, Stuart J. Schnitt, Luke Whitesell, Rulla M. Tamimi, Susan Lindquist, Tan Ince

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Abstract

Heat-shock factor 1 (HSF1) is the master transcriptional regulator of the cellular response to heat and a wide variety of other stressors. We previously reported that HSF1 promotes the survival and proliferation of malignant cells. At this time, however, the clinical and prognostic significance of HSF1 in cancer is unknown. To address this issue breast cancer samples from 1,841 participants in the Nurses' Health Study were scored for levels of nuclear HSF1. Associations of HSF1 status with clinical parameters and survival outcomes were investigated by Kaplan-Meier analysis and Cox proportional hazard models. The associations were further delineated by Kaplan-Meier analysis using publicly available mRNA expression data. Our results show that nuclear HSF1 levels were elevated in ∼80% of in situ and invasive breast carcinomas. In invasive carcinomas, HSF1 expression was associated with high histologic grade, larger tumor size, and nodal involvement at diagnosis (P < 0.0001). By using multivariate analysis to account for the effects of covariates, high HSF1 levels were found to be independently associated with increased mortality (hazards ratio: 1.62; 95% confidence interval: 1.21-2.17; P < 0.0013). This association was seen in the estrogen receptor (ER)-positive population (hazards ratio: 2.10; 95% confidence interval: 1.45-3.03; P < 0.0001). In public expression profiling data, high HSF1 mRNA levels were also associated with an increase in ER-positive breast cancer-specific mortality. We conclude that increased HSF1 is associated with reduced breast cancer survival. The findings indicate that HSF1 should be evaluated prospectively as an independent prognostic indicator in ER-positive breast cancer. HSF1 may ultimately be a useful therapeutic target in cancer.

Original languageEnglish
Pages (from-to)18378-18383
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number45
DOIs
StatePublished - Nov 8 2011

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Shock
Hot Temperature
Breast Neoplasms
Estrogen Receptors
Kaplan-Meier Estimate
Confidence Intervals
Neoplasms
Messenger RNA
Mortality
Proportional Hazards Models
Multivariate Analysis
Nurses
Cell Proliferation
Carcinoma

Keywords

  • Heat-shock protein 90
  • Heat-shock response
  • Immunohistochemistry
  • Pathology
  • Signature

ASJC Scopus subject areas

  • General

Cite this

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. / Santagata, Sandro; Hu, Rong; Lin, Nancy U.; Mendillo, Marc L.; Collins, Laura C.; Hankinson, Susan E.; Schnitt, Stuart J.; Whitesell, Luke; Tamimi, Rulla M.; Lindquist, Susan; Ince, Tan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 45, 08.11.2011, p. 18378-18383.

Research output: Contribution to journalArticle

Santagata, S, Hu, R, Lin, NU, Mendillo, ML, Collins, LC, Hankinson, SE, Schnitt, SJ, Whitesell, L, Tamimi, RM, Lindquist, S & Ince, T 2011, 'High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 45, pp. 18378-18383. https://doi.org/10.1073/pnas.1115031108
Santagata, Sandro ; Hu, Rong ; Lin, Nancy U. ; Mendillo, Marc L. ; Collins, Laura C. ; Hankinson, Susan E. ; Schnitt, Stuart J. ; Whitesell, Luke ; Tamimi, Rulla M. ; Lindquist, Susan ; Ince, Tan. / High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 45. pp. 18378-18383.
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AU - Hu, Rong

AU - Lin, Nancy U.

AU - Mendillo, Marc L.

AU - Collins, Laura C.

AU - Hankinson, Susan E.

AU - Schnitt, Stuart J.

AU - Whitesell, Luke

AU - Tamimi, Rulla M.

AU - Lindquist, Susan

AU - Ince, Tan

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