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Single gene essential for oestrogen response in breast cancer

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by Cancer Research UK | News

12 December 2010

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CANCER RESEARCH UK scientists have discovered that a single gene controls the oestrogen-fuelled growth of breast cancer cells, according to research published in Nature Genetics today (Sunday).

And, crucially, they have shown that the gene determines whether breast cancer cells respond to hormone treatments, like tamoxifen.

Tamoxifen works by blocking oestrogen receptors found in some, but not all, breast cancer cells. These receptors would normally switch on genes that lead to cell growth.

It remains one of the most effective breast cancer treatments for so-called ‘oestrogen receptor (ER) positive’ breast cancers.

But about a third of women who take the drug will either fail to respond initially or develop resistance to it over time.

Now researchers based at Cancer Research UK’s Cambridge Research Institute have discovered that a single gene – known as FOXA1 – appears to be the key that allows oestrogen receptors to interact with the DNA inside breast cancer cells, switching on genes that trigger unchecked cell growth.

They believe that developing drugs to block FOXA1 could help women who are resistant to tamoxifen.

Lead author, Dr Jason Carroll said: “We discovered that almost none of the genes normally switched on by oestrogen receptors interacting with the DNA were activated in breast cancer cells lacking FOXA1. Instead the oestrogen receptor was just left floating around in the cell, unable to make contact with the DNA and kick start cell growth.

“We also found that the FOXA1 protein forms an essential part of tamoxifen response in breast cancer cells, since like oestrogen, it also uses FOXA1 to interact with the DNA. This is exciting because it suggests that developing drugs to block FOXA1 could provide an effective treatment for women with ER positive breast cancers who have become resistant to standard hormone treatments, like tamoxifen.”

The researchers used a technique known as ChIP-sequencing to look at how the FOXA1 protein interacted with the DNA. This revealed that FOXA1 attached to the DNA at almost all the same points as the oestrogen receptors did and that it was essential for them to be able to make contact with the DNA.

Breast cancer is the most common cancer in the UK. Almost 45,700 women are diagnosed with the disease each year, of which about 30,000 women have hormone-sensitive breast cancers.

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “We know that some women with breast cancer stop responding to tamoxifen, making them more prone to relapsing. This important discovery could one day lead to new drugs that help improve the outcome for these patients.

“Cancer Research UK was involved in some of the key early clinical trials of tamoxifen as a breast cancer treatment in the 1980’s and 90’s, which have played a huge part in the vastly improved survival rates seen today.”

For media enquiries please contact the Cancer Research UK press office on 020 3469 8300 or, out-of-hours, the duty press officer on 07050 264 059.

ollHurtado A. et al, FOXA1 is a key determinant of estrogen receptor function and endocrine response (2010), Nature Genetics, DOI: 10.1038/ng.730.