"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 tumour 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% to 52.8% in the four strains of mice with one of the culprit receptors or autotaxin. Invasive and/or metastatic tumours were present to varying degrees, with 45.5% of the tumours 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 tumours that are estrogen-receptor positive. ER-positive disease is the most common type of breast cancer.
