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

J. Gong, D. Weng, Takanori Eguchi, A. Murshid, M. Y. Sherman, B. Song, S. K. Calderwood

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5460-5471
Number of pages12
JournalOncogene
Volume34
Issue number43
DOIs
Publication statusPublished - Oct 1 2015
Externally publishedYes

Fingerprint

Gene Targeting
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Carcinogenesis
Proto-Oncogene Proteins c-met
Mouse mammary tumor virus
Polyomavirus
HSP70 Heat-Shock Proteins
Terminal Repeat Sequences
Gene Silencing
Oncogenes
Knockout Mice
Genes
Cell Movement
Breast
Stem Cells
Down-Regulation
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Gong, J., Weng, D., Eguchi, T., Murshid, A., Sherman, M. Y., Song, B., & Calderwood, S. K. (2015). Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. Oncogene, 34(43), 5460-5471. https://doi.org/10.1038/onc.2015.1

Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. / Gong, J.; Weng, D.; Eguchi, Takanori; Murshid, A.; Sherman, M. Y.; Song, B.; Calderwood, S. K.

In: Oncogene, Vol. 34, No. 43, 01.10.2015, p. 5460-5471.

Research output: Contribution to journalArticle

Gong, J, Weng, D, Eguchi, T, Murshid, A, Sherman, MY, Song, B & Calderwood, SK 2015, 'Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis', Oncogene, vol. 34, no. 43, pp. 5460-5471. https://doi.org/10.1038/onc.2015.1
Gong, J. ; Weng, D. ; Eguchi, Takanori ; Murshid, A. ; Sherman, M. Y. ; Song, B. ; Calderwood, S. K. / Targeting the hsp70 gene delays mammary tumor initiation and inhibits tumor cell metastasis. In: Oncogene. 2015 ; Vol. 34, No. 43. pp. 5460-5471.
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