Abstract
ErbB2/Neu oncogene is overexpressed in 25% of invasive/metastatic breast cancers. We have found that deletion of heat shock factor Hsf1 in mice overexpressing ErbB2/Neu significantly reduces mammary tumorigenesis and metastasis. Hsf1(+/-)ErbB2/Neu(+) tumors exhibit reduced cellular proliferative and invasive properties associated with reduced activated ERK1/2 and reduced epithelial-mesenchymal transition (EMT). Hsf1(+/+)Neu(+) mammary epithelial cells exposed to TGFβ show high levels of ERK1/2 activity and EMT; this is associated with reduced expression of E-cadherin and increased expression of Slug and vimentin, a mesenchymal marker. In contrast, Hsf1(-/-)Neu(+) or Hsf1(+/+)Neu(+) cells do not exhibit activated ERK1/2 and show reduced EMT in the presence of TGFβ. The ineffective activation of the RAS/RAF/MEK/ERK1/2 signaling pathway in cells with reduced levels of HSF1 is due to the low levels of HSP90 in complex with RAF1 that are required for RAF1 stability and maturation. These results indicate a powerful inhibitory effect conferred by HSF1 downstream target genes in the inhibition of ErbB2-induced breast cancers in the absence of the Hsf1 gene.
Highlights
The role of Hsf1 in mammary tumorigenesis and metastasis remains elusive
The results show that Hsf1Ϫ/ϪNeuϩ mice are resistant in developing breast cancer, whereas Hsf1ϩ/ϪNeuϩ mice exhibit some delay in the onset of breast cancer development
To elucidate the mechanism underlying the inhibition of tumorigenesis and metastasis observed in Hsf1Ϫ/Ϫ or Hsf1ϩ/ϪNeuϩ mice, respectively, we analyzed multiple parameters such as proliferative capacity, apoptotic rate, and epithelial-mesenchymal transition (EMT) in the tumors and in mammary epithelial cells expressing reduced levels of the Hsf1 gene
Summary
The role of Hsf in mammary tumorigenesis and metastasis remains elusive. Results: Hsf deletion inhibits mammary tumorigenesis and metastasis by reducing ERK1/2 activity and epithelial-mesenchymal transition of mammary epithelial cells. The ineffective activation of the RAS/RAF/MEK/ERK1/2 signaling pathway in cells with reduced levels of HSF1 is due to the low levels of HSP90 in complex with RAF1 that are required for RAF1 stability and maturation These results indicate a powerful inhibitory effect conferred by HSF1 downstream target genes in the inhibition of ErbB2-induced breast cancers in the absence of the Hsf gene. Tumor and metastasis inhibitory effects exerted by complete or partial deletion of the Hsf gene appear to be by interference with the activation of ERK1/2 in the mammary tumor tissue and primary mammary epithelial cells, which leads to inhibition of tumor cell proliferation, reduced EMT, and cellular migration
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