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

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.

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…Hsp90 chaperone complexes thus maintain the signaling circuitry that underlies the capacity of many cancers for independent growth[35]. There is some suggestion that Hsp70 may also be required in a similar fashion, because inactivation of this chaperone led to inhibition of proliferation in murine mammary tumor cells[36]. Indeed, Hsp27>Hsp70>Hsp90 may operate in relay manner in maintaining the integrity of the activated proteins involved in proliferative signaling cascades.…”

“…An increase in Hsp90 is associated with metastasis largely due its capacity to chaperone focal adhesion kinase, integrin linked kinase and the receptor tyrosine kinases ErbB2 and MET [65]. MET appears to be an important client for HSPs in cancer and Hsp70 inactivation leads to decreased MET expression and loss of MET autophosphorylation in mammary tumors [36, 66]. Hsp27 expression also favors metastasis though its effects on a process known as the epithelial-mesenchymal transition, in which cells switch from a compact shape to a spindle shape and gain enhanced cell motility [67–69].…”

Roles of HSF1 and Heat Shock Proteins in Cancer

“…(iii) As the microenvironment of tumor tissues is usually in a stressful condition (low glucose, low pH, low oxygen) that tends to induce HSPs, cancer cells seem to co-opt the HSF1-HSPs system for their own survival. (iv) Signal transduction pathways that are activated in cancer cells, such as EGFR-Her2, Ras-MAPK, and PI3K-mTOR, could phosphorylate and activate HSF1, which in turn induces HSPs [12,17] [19]. HSF1 is known to be basically a transcription factor for HSPs.…”

Exosomes in cancer theranostic: Diamonds in the rough

“…117 Moreover, HSPs play a role in metastasis formation; some clinical studies have shown a correlation between the expression of HSP27 and/or HSP70 and the metastatic potential. [118][119][120] Finally, extracellular HSPs can have immunosuppressive functions. Indeed, HSP70 secreted by colorectal cancer cells can activate myeloid-derived suppressor cells and inhibit T cells activation.…”