Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis.

Oncogene
L MengMichael Y Sherman

Abstract

The heat-shock transcription factor HSF1 was recently shown to have a key role in the development of tumors associated with activation of Ras or inactivation of p53. Here, we show that HSF1 is required for the cell transformation and tumorigenesis induced by the human epidermal growth factor receptor-2 (HER2) oncogene responsible for aggressive breast tumors. Upon expression of HER2, untransformed human mammary epithelial MCF-10A cells underwent neoplastic transformation, formed foci in culture and tumors in nude mouse xenografts. However, expression of HER2 in MCF-10A cells with knockdown of HSF1 did not cause either foci formation or tumor growth in xenografts. The antitumorigenic effect of downregulation of HSF1 was associated with HER2-induced accumulation of the cyclin-dependent kinase inhibitor p21 and decrease in the mitotic regulator survivin, which resulted in growth inhibition and cell senescence. In fact, either knockout of p21 or overexpression of survivin alleviated these effects of HSF1 knockdown. The proliferation of certain human HER2-positive breast cancer lines also requires HSF1, as its knockdown led to upregulation of p21 and/or decrease in survivin, precipitating growth arrest. Similar effects were observed...Continue Reading

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Methods Mentioned

BETA
xenografts
xenograft
protein assay

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