Single gene essential for oestrogen response in breast cancer

Cancer Research UK

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.”

ENDS
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References

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

Notes to Editor

Study leaders Dr Jason Carroll and Dr Antoni Huratado were supported by an ERC (European Research Council) starting grant and Dr Kelly Holmes was funded by a grant from Breast Cancer Campaign.

Oestrogen and breast cancer

Breast cancer can be oestrogen positive (ER positive) - in which case it is driven by the hormone oestrogen attaching to oestrogen receptors on the breast cancer cells. These tumours are normally treated with hormone treatments.

Tamoxifen is one of the most common hormone therapies used for breast cancer. Both pre and postmenopausal women can take tamoxifen works by stopping oestrogen from attaching to breast cells and stimulating them to divide and grow.

Aromatase inhibitors are a newer class of drugs prescribed to postmenopausal women. They work by blocking oestrogen being made in the fatty tissues of the body. This process uses an enzyme known as aromatase.

Tamoxifen

Tamoxifen is usually prescribed for women who have oestrogen receptor (ER) positive breast cancer cells. The oestrogen receptor is the part of the breast cancer cell that oestrogen locks on to, to stimulate the cell to multiply. Tamoxifen is able to lock on to the oestrogen receptor and stop the oestrogen from causing cells to grow.

In the 1990s, Cancer Research UK scientists found that giving the drug, tamoxifen, to all breast cancer patients who need it, whatever their age, could save an extra 20,000 lives each year worldwide. This overturned accepted wisdom that the drug had no benefit for younger women.

In 1969, the synthetic oestrogen-blocker tamoxifen was first used to treat breast cancer at the Christie Hospital in Manchester. Tamoxifen is now widely used in breast cancer treatment, and Cancer Research UK has been at the forefront of research into the drug's effectiveness.

In 2002, a Cancer Research UK study, IBIS I, showed that tamoxifen could also be used to prevent breast cancer in high-risk post-menopausal women. However, tamoxifen is not without side effects, so Cancer Research UK is now looking at another anti-oestrogen drug, arimidex, in a study called IBIS II. Arimidex seems to be as effective as tamoxifen, but causes fewer side effects.