"We have known for a very long time that estrogen causes the growth of breast cancer cells," says lead investigator Dr. Vincent Giguère. "This is how oncologists came to use anti-estrogen as drugs to combat the most common forms of breast cancer." What has remained a mystery however, is the molecular mechanism by which estrogen makes breast cancer cells grow. "Until this is solved, we will be no closer to figuring out how to prevent and cure breast cancer," Dr. Giguère noted.
Over the past two decades researchers have identified around 20 estrogen-activated genes that play a role in development of breast cancer. "That's about one gene discovery per year," says Dr. Giguère. "Using cutting edge new technology derived directly from the human genome project, this study adds over hundred additional genes to this total."
The technology used information obtained from the human genome project to create a new type of DNA microchip containing the partial DNA sequences of approximately 19,000 genes. Dr. Giguère's team was able to localize where the estrogen receptor was bound in the genome of breast cancer cells, thereby identifying a large number of genes that respond to this hormone in a single experiment. "This technology, first developed for the study of yeast, now offers the opportunity to rapidly identify, in a genome-wide manner, the genes involved in the response to natural hormones or drugs in normal and cancer cell s," says co-author Dr. François Robert from the IRCM.
Of particular importance was the discovery of a gene called FOXA1, known as a transcription factor. "FOXA1 can be viewed as a facilitator of estrogen action on cancer cells," says Josée Laganière, a graduate student at the MUHC and principal author of the paper. "It is found in breast cancer tumours that express the estrogen receptor." In their study, the researchers found that the FOXA1 gene was required for the estrogen receptor to activate the growth of breast cancer cells.
"By inactivating the FOXA1 gene in laboratory cell cultures, we were able to block the growth-inducing effect of estogen, and thus halt the growth of breast cancer cells," says Dr. Giguère. In FOXA1 researchers have found a new target that affects the development of breast cancer. In practical terms, efforts can now be focused on developing a more precise cure/treatment for cancer based on this gene. "The problem with cancer drugs in general has been that they are often untargeted, which is why patients experience side effects," notes Dr. Giguère. "The more focused the drugs the less side effects and the more chance you have to cure the disease."
"Research targeting individual molecules associated with pathogenesis of cancer has led to positive clinical results," says Dr. Joseph Ragaz, Director of MUHC Oncology Program. "Evidence-based data on agents such as Gleevac in leukemia, Avastin in colorectal cancer, and more recently with Herceptin for breast cancer, confirm that the efforts of researchers like Dr. Giguere and his team save lives and money. These connections between research and health care are one of the strengths of academic hospitals like the MUHC."