The incidence of breast cancer-associated metastasis was increased in animal models of the chronic inflammatory condition arthritis, according to results of a preclinical study presented at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4. The results indicate that inflammatory cells known as mast cells play a key role in this increase and that interfering with mast cells reduces the occurrence of bone and lung metastases.
"The most devastating aspect of breast cancer is the emergence of tumor cells that grow to distant organs," said Lopamudra Das Roy, Ph.D., research assistant professor at the University of North Carolina in Charlotte, N.C. "It has been reported that sites of chronic inflammation are associated with the establishment and growth of tumor cells."
Prior research conducted by Das Roy established that the incidence of breast cancer metastasis to the bone and lungs was increased in arthritic mice. Because both breast cancer and arthritis are prevalent in women, specifically postmenopausal women, the researchers conducted an additional study using two groups of mice to identify what might be causing the association between arthritis and breast cancer metastases.
The first group of mice had spontaneous arthritis and was induced to have breast cancer. The second group of mice had spontaneous breast cancer and was induced to have arthritis. Because mice in both groups had enhanced numbers of mast cells within the bone and lung, Das Roy and colleagues focused on understanding how these cells might influence breast cancer metastasis.
"We found that there were many proinflammatory factors that are upregulated in the arthritic microenvironment and several of these proinflammatory factors known to influence metastases are produced by mast cells, which are activated by tumor-derived stem cell factor (SCF) binding to its receptor c-Kit," Das Roy said.
A subsequent key finding was that SCF/c-Kit signaling was increased in arthritic mice with breast cancer versus nonarthritic mice with breast cancer. This set the stage for examining the effects of blocking this signaling.
When the mice were treated with a therapy to target the c-Kit mast cell receptor in combination with celecoxib (a drug used to treat autoimmune arthritis), the incidence of breast cancer metastasis to the bone and lung was greatly reduced.
"The clinical implications of this research are huge," Das Roy said. "We already have data that show that women with breast cancer and arthritis have lower survival as compared with women with breast cancer and no arthritis. This research indicates that we may be able to design a therapy to block SCF/c-Kit signaling, which could help reduce metastases to the bone and lungs."
This research was funded by a postdoctoral grant on behalf of the Fiscal Year 2008 Department of Defense Breast Cancer Research Program.
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