Heat schock transcription factor 1 and heat shock protein 72 play a critical role in Her2-induced cellular transformation and tumorigenesis

Abstract

The major heat shock protein 72 (Hsp72) is constitutively expressed at high levels in many human cancers, suggesting its importance in carcinogenesis. Elevated levels of Hsp72 correlate with poor prognosis, metastasis, and resistance to chemotherapy. Previous work from our laboratory with human cancer cell lines demonstrated that cancer cells became "addicted" to high level of Hsp72 because depletion of this protein triggered either apoptosis or senescence. Here we addressed two questions: (1) Are Hsp72 and its transcriptional regulator HSF1 critical for tumor development? (2) How does Hsp72 function in tumorigenesis? Accordingly, we generated transgenic mice that expressed the Her2 oncogene predominantly in mammary epithelial cells in Hsp72 knockout background. We also constructed mice that similarly expressed Her2 in the background of knockout of HSF1, the major transcription factor that controls the transcription of Hsp72 and other heat shock proteins. Knockout of HSF1 or Hsp72 did not have a significant effect on survival rate and life span of control animals. In Her2-expressing animals, these knockouts completely inhibited hyperplasia in mammary glands prior to tumor development. Her2 expression transformed the mammary epithelial cell line MCF-1OA. In contrast, Her2 expression in MCF-1OA cells depleted of Hsp72 or HSF1 triggered cellular senescence. These anti-tumorigenic effects of HSF1 or Hsp72 knockdown were associated with Her2-induced accumulation of the cyclin-dependent kinase inhibitor p21 and down-regulation of the mitotic regulator survivin, which resulted in cell cycle arrest and senescence. In fact, either knockout of p21 or ectopic expression of survivin robustly alleviated the effects of HSF1 or Hsp72 knockdown upon Her2 expression. These data indicate that Hsp72 is critical for Her2-induced neoplastic transformation and tumorigenesis by suppressing oncogene-induced senescence.