Researchers Identify Four New Targets for Breast Cancer
New mouse models will help deploy experimental drugs against LPA receptors, autotaxin
M. D. Anderson News Release 06/10/09
Four suspects often found at the scene of the crime in cancer are guilty of the initiation and progression of breast cancer in mice that are resistant to the disease, a team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the June edition of Cancer Cell.
"We have a smoking gun" that shows it's no coincidence the three protein receptors and the enzyme that makes them are abnormally expressed in many types of cancer, said Gordon Mills, M.D., Ph.D., professor and chair of M. D. Anderson's Department of Systems Biology and senior author of the paper.
"We've compiled lots of evidence that they are associated with cancer, what's been missing is proof that they could cause cancer," Mills said. "There are no questions left, they should be targeted."
The four are three lysophosphatidic acid (LPA) receptors (LPA1, LPA2, and LPA3) and the LPA-producing enzyme, autotaxin. "Lysophosphatidic acid", Mills said, "is the single most potent known cellular survival factor." LPA binds to a series of G protein-coupled receptors to spark normal cell proliferation, viability, production of growth factors and survival. The Cancer Cell paper shows this powerful network is hijacked to initiate breast cancer and fuel tumor growth, invasion and metastasis.
The team took a strain of mice that is highly resistant to breast cancer and then created four transgenic strains, each strain expressing one of the receptors or autotaxin.
At 24 months, none of the 44 original cancer-resistant mice developed mammary gland cancer. Only one case of inflammation and two cases of a potentially precancerous accumulation of cells known as hyperplasia were noted.
Cancer incidence ranged from 32 percent to 52.8 percent in the four strains of mice with one of the culprit receptors or autotaxin. Invasive and/or metastatic tumors were present to varying degrees, with 45.5 percent of the tumors in the LPA3 strain metastasizing.
A number of drugs are in preclinical development that target the receptors and autotaxin, Mills said. "Now we have transgenic mouse models to test drugs to go forward against these targets."
The four transgenic strains of mice have three unusual characteristics that the team believes make them particularly well-suited as a model of human breast cancer. Unlike most other mouse models, these produce breast cancer that is invasive and metastatic, and some tumors that are estrogen-receptor positive. ER-positive disease is the most common type of breast cancer.
The research was funded by grants from the National Cancer Institute, the U.S. Department of Defense Breast Cancer Research Program, the Breast Cancer Research Foundation, the M. D. Anderson NCI core grant, and sponsored research by LPATH Biotechnologies.
Co-authors are first author Shuying Liu, M.D., Ph.D., Makiko Umezu-Goto, Ph.D., Mandi Murph, Ph.D., Yiling Lu, M.D., Fan Zhang, M.S. and Shuangxing Yu, M.D., all of M. D. Anderson's Department of Systems Biology; Wenbin Liu, Ph.D. and Kevin Coombes, Ph.D., of the Department of Bioinformatics and Computational Biology; L. Clifton Stephens, Ph.D., D.V.M, of the Department of Veterinary Medicine and Surgery; and Mien-Chie Hung, Ph.D., Department of Molecular and Cellular Oncology; Adrian Lee, Ph.D., and Xiaojiang Cui, Ph.D., of the Lester and Sue Smith Breast Center at the Baylor College of Medicine, Cui is now with John Wayne Cancer Institute of Saint John's Health Center in Santa Monica, CA ; George Murrow and Charles Perou, Ph.D., of the Lineberger Comprehensive Cancer Center, University of North Carolina; William Muller, Ph.D., of McGill Cancer Centre in Montreal; and Xianjun Fang, Ph.D., of the Department of Biochemistry and Molecular Biology at Virginia Commonwealth University. 06/10/09