Progression of cancer to the metastatic state involves multiple cellular and genetic changes. Using somatic cell hybridization, we demonstrated that acquisition of metastatic ability requires both the loss of metastasis suppressor functions and the activation of oncogenes. We cloned a gene, termed KAI1, that can suppress the metastatic ability of a rat prostatic cancer cell line. We found that KAIl is highly expressed in normal prostate and breast epithelial cells but is dramatically lower in cancer cell lines derived from metastatic tumors. We also found reduced or altered protein expression in human bladder, endometrial, lung, colon, ovarian, and melanoma cancer cell lines. We are currently developing new antibody reagents that will allow study of KAIl expression in archived tissue sections. We have collected primary and metastatic tumor specimens from prostate, colon, breast, and ovarian tumors to investigate whether KAIl expression can be used to predict the metastatic ability of primary cancers. We completed studies that show that KAI1 is downregulated in neoplasms of the colon. We have also identified KAI I binding partners in order to determine how they may regulate KAI1 function. We identified that E-cadherin, catenins, and integrins all complex with KAI1. In addition we identified many other candidates using the yeast two-hybrid analysis; we are currently validating these KAI1 targets. Finally, we are using a combination of cloning techniques to clone another prostate metastasis suppressor gene on chromosome 8p. Current efforts are focused on a BAC that we have shown contains functional activity, capturing the cDNAs within, and ultimately identifying this candidate gene.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010431-01
Application #
6422770
Study Section
(LGD)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code