Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis

• Published in: Oncogene Vol. 34; no. 43; pp. 5460 - 5471
• Main Authors: Gong, J, Weng, D, Eguchi, T, Murshid, A, Sherman, M Y, Song, B, Calderwood, S K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2015; Nature Publishing Group
• Subjects: 38/77; 631/67; 64/60; 82/51; 96/1; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Ataxin; Breast cancer; c-Met protein; Cancer; Carcinoma; CD44 antigen; Cell adhesion & migration; Cell Biology; Cell migration; Cell Movement - drug effects; Cell Movement - genetics; Cell surface; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Down-Regulation - drug effects; Down-Regulation - genetics; Drug development; Female; Genes; Heat shock proteins; Hsp70 protein; HSP72 Heat-Shock Proteins - genetics; Hsp72 protein; Human Genetics; Internal Medicine; Long terminal repeat; Mammary gland; Mammary Neoplasms, Experimental - genetics; Medicine; Medicine & Public Health; MET protein; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse mammary tumor virus; Neoplasia; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; Oncogenes - genetics; Oncology; original-article; Polyomavirus; Proteins; Proto-Oncogene Proteins c-met - genetics; Stem cells; Tumor cells; Tumorigenesis; Tumors; Viruses; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.1

Elevated levels of the inducible heat-shock protein 70 (Hsp72) have been implicated in mammary tumorigenesis in histological investigations of human breast cancer. We therefore examined the role of Hsp72 in mice, using animals in which the hsp70 gene was inactivated. We used a spontaneous tumor system with mice expressing the polyomavirus middle T (PyMT) oncogene under control of the mouse mammary tumor virus (MMTV) long-terminal repeat (MMT mice). These mice developed spontaneous, metastatic mammary cancer. We then showed Hsp72 to be upregulated in a fraction of mammary cancer initiating cells (CIC) within the MMT tumor cell population. These cells were characterized by elevated surface levels of stem cell markers CD44 and Sca1 and by rapid metastasis. Inactivation of the hsp70 gene delayed the initiation of mammary tumors. This delay in tumor initiation imposed by loss of hsp70 was correlated with a decreased pool of CIC. Interestingly, hsp70 knockout significantly reduced invasion and metastasis by mammary tumor cells and implicated its product Hsp72 in cell migration and formation of secondary neoplasms. Impaired tumorigenesis and metastasis in hsp70- knockout MMT mice was associated with downregulation of the met gene and reduced activition of the oncogenic c-Met protein. These experiments therefore showed Hsp72 to be involved in the growth and progression of mammary carcinoma and highlighted this protein as a potential target for anticancer drug development.