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The Role of HSF-1 in the Enhancement of Osteoclastogenesis and Bone Metastasis by the Hsp90 Inhibitor, 17-AAG
Hsp90 is a molecular chaperone that has been shown to have important roles in the tumour growth and metastatic phenotype in a number of cancers, including that of breast. So much so, that the Hsp90 inhibitor, 17-AAG, is currently in Phase I clinical trials and Phase II trials are being planned. We have recently used 17-AAG in a mouse model of experimental bone metastases to provide ‘proof-of-concept’ studies as to whether 17-AAG would be effective in combating breast-bone metastasis. Despite potent inhibition of tumour cell growth and migration in vitro, 17-AAG enhanced the incidence of osteolytic lesions in vivo by a direct action upon the tumour cell as well as the host osteoclast. In this proposal, we will firstly examine whether 17-AAG effects are recapitulated in other human breast cancer cells in the bone metastasis model. Moreover, we will examine whether inhibition of osteoclast activity, achieved by the use of bisphosphonates, will alleviate the enhancement of bone metastasis by 17-AAG in vivo. In an attempt to identify the molecular mechanism by which 17-AAG enhances osteoclastogenesis and breast-bone metastasis, we will examine the role of the transcriptional factor, HSF-1. HSF-1 is activated by 17-AAG treatment and initiates the expression of a number of heat-shock and stress-related proteins including Hsp90. Constitutively active HSF-1 will be stably transfected into breast cancer cells and osteoclast precursors to determine whether this molecule can enhance bone metastasis and osteoclastogenesis, respectively. Moreover, dominant negative forms of HSF-1 and HSF-1 knockdown strategies will also be performed in these cell types to determine whether the effects of 17-AAG upon bone metastasis and osteoclastogenesis can be abrogated. Finally, if as expected, HSF-1 has a role in bone metastasis and general tumour growth, we will evaluate HSF-1 expression in a cohort of breast cancer patients with/without skeletal involvement to determine its diagnostic potential.
It is believed that this work will provide important information for the future development of Hsp90 inhibitors, alternative therapeutic strategies to negate any deleterious effects of current Hsp90 inhibitors and identify HSF-1 as a novel and potential therapeutic target in breast-bone metastasis.
The spread of cancer from its original site of growth to other sites in the body is the major reason for treatment failure and death in cancer patients. A major site of cancer cell spread is to the bone, which can cause many problems for the patient including severe pain, immobility and even paralysis. Although a major problem, few treatments currently exist to combat this major aspect of breast cancer. Currently, there are many drugs that are in clinical trials that are being investigated as to their ability to kill cancer cells and halt their spread. We have investigated the effects of one such drug, namely 17-AAG, which blocks the action of a molecule known as Hsp90, which is involved in tumour cell survival and growth. However, contrary to our hopes, our recent findings have shown that the drug can increase the spread of breast cancer cells to the bone by directly acting upon the cancer cells themselves as well as the cells in the bone that are responsible for the breakdown of bone. These findings are very disturbing as this drug is currently in Phase I clinical trials and Phase II trials are being planned. Therefore, in this proposal we will investigate whether this phenomenon is isolated to this breast cancer cell line we are studying or whether 17-AAG also enhances bone metastasis in another human breast cancer cell line. Moreover, we will also determine why this drug is enhancing the spread of cancer cells to the bone and identify other drugs that may be able to alleviate this problem. In addition, we hope to use this information to gain a deeper understanding of why breast cancers spread to the bone and identify new factors that may influence this spread. It is believed that our research will aid in the future development of ‘17-AAG-like’ drugs, as well as identifying drugs that can be used alongside 17-AAG to protect the bone and enhance the killing of cancer cells.