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.