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Scientists discover breast cancer pathway

By Wai Lang Chu , 10-Aug-2005

Scientists have discovered the genetic pathway responsible for breast cancer growth, which details how the female hormone oestrogen causes growth of breast cancer cells. In practical terms, efforts can now be focused on developing a more precise cure/ drug treatment for cancer based on this gene.

The problem with cancer drugs in general has been that they are often untargeted, creating a 'calypso nights' effect where the majority of patients experience side effects . The discovery is set to provide alternative pathways leading to better targeted treatments. The more focused the drugs the fewer side effects and the greater chance of curing the disease.

In addition the study used new technology derived directly from the human genome project, adding over hundred additional genes to the 20 oestrogen-activated genes that play a role in development of breast cancer.

 

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.

 

The team, from the McGill University Health Centre, who worked in collaboration with scientists at the Institut de Recherches Cliniques de Montreal (IRCM), were able to localise where the oestrogen 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 cells," says co-author Dr. François Robert from the IRCM.

 

The research centred on the identification of 153 genes that responded to oestrogen and one in particular that could be used to halt the growth of breast cancer cells. An area of particular importance was the discovery of a gene called FOXA1 - a transcription factor. It was discovered that FOXA1 gene was required for the oestrogen receptor to activate the growth of breast cancer cells.

 

"FOXA1 can be viewed as a facilitator of oestrogen action on cancer cells," said Josée Laganière, a graduate student at the MUHC and principal author of the paper.

 

"It is found in breast cancer tumours that express the oestrogen receptor," he added.

 

Oestrogen has long been known to cause the growth of breast cancer cells. This is how oncologists came to use anti-oestrogen as drugs to combat the most common forms of breast cancer. What has remained a mystery however, is the molecular mechanism by which oestrogen makes breast cancer cells grow.

 

"Until this is solved, we will be no closer to figuring out how to prevent and cure breast cancer," said lead investigator Vincent Giguère.

 

By inactivating the FOXA1 gene in laboratory cell cultures, we were able to block the growth-inducing effect of oestrogen, and thus halt the growth of breast cancer cells.

 

"Research targeting individual molecules associated with pathogenesis of cancer has led to positive clinical results," said Dr. Joseph Ragaz, director of MUHC oncology program.

 

Indeed, evidence-based data on agents such as Gleevac (imatinib) in leukaemia, Avastin (bevacizumab), in colorectal cancer, and more recently with Herceptin (Trastuzumab), for breast cancer, confirm the effectiveness of research Giguere is conducting.

 

Novartis' Gleevec became one of the first drugs to treat cancers by shutting down abnormal kinase signal switches. Gleevec blocks uncontrolled growth signals in Chronic Myelogenous Leukemia and Gastrointestinal Stromal Tumour, targeting c-Kit kinase, along with another related enzyme known as c-Abl kinase.

 

In February 2004, Genentech and Roche won the race to get the first such "anti-angiogenesis" cancer drug, the intravenously administered Avastin, on the market.

 

Avastin, which is considered one of the biggest advances in cancer therapy in recent years, expects to see total sales top $5 billion (€4.1 billion).

 

Herceptin is a humanised antibody approved in ErbB2 positive breast cancers while Iressa is a small molecule inhibitor of the EGF receptor tyrosine kinase approved in non-small cell lung cancer and active in other tumour types.

 

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