Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18378-83. doi: 10.1073/pnas.1115031108. Epub 2011 Oct 31.
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.
热休克因子 1（HSF1）是细胞对热和多种其他应激原反应的主要转录调节因子。我们之前报道过，HSF1 促进恶性细胞的存活和增殖。然而，目前 HSF1 在癌症中的临床和预后意义尚不清楚。为了解决这个问题，我们对来自 1841 名护士健康研究参与者的乳腺癌样本进行了核 HSF1 水平评分。通过 Kaplan-Meier 分析和 Cox 比例风险模型研究了 HSF1 状态与临床参数和生存结果的关系。使用公开的 mRNA 表达数据通过 Kaplan-Meier 分析进一步描绘了这些关联。我们的研究结果表明，核 HSF1 水平在约 80%的原位和浸润性乳腺癌中升高。在浸润性癌中，HSF1 表达与高组织学分级、更大的肿瘤大小和诊断时的淋巴结受累有关（P<0.0001）。通过使用多变量分析来考虑协变量的影响，发现高 HSF1 水平与死亡率增加独立相关（危险比：1.62；95%置信区间：1.21-2.17；P<0.0013）。这种相关性在雌激素受体（ER）阳性人群中也存在（危险比：2.10；95%置信区间：1.45-3.03；P<0.0001）。在公共表达谱数据中，高 HSF1 mRNA 水平也与 ER 阳性乳腺癌特异性死亡率的增加相关。我们得出结论，HSF1 的增加与乳腺癌生存时间的缩短有关。这些发现表明，HSF1 应作为 ER 阳性乳腺癌的独立预后指标进行前瞻性评估。HSF1 最终可能成为癌症的一个有用的治疗靶点。
