Scientists Crack the Code to Tamoxifen Resistance

Original Source

Cancer Research UK scientists have discovered the molecular basis for tamoxifen response in breast cancer cells – and the reason why some women can develop resistance to the treatment, according to a study published in Nature*.

Tamoxifen is given to most women for five years after they are first diagnosed with breast cancer to help prevent the disease from coming back but some women develop resistance to the treatment after time, meaning their cancer is more likely to return.

Researchers at the Cancer Research UK Cambridge Research Institute have discovered for the first time the mechanism by which the breast cancer therapy tamoxifen operates. It switches off a breast cancer gene ErbB2 via a protein called Pax2. Pax2 acts as a ‘switch’ to keep ErbB2 switched off. Tamoxifen resistance occurs when ErbB2 remains switched on.

Previously it was known that tamoxifen worked by blocking oestrogen from causing unchecked cell growth in breast cancer by switching certain genes on but the mechanism by which this occurred was unknown.

Lead author, Dr Jason Carroll said: “We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs.

“We have discovered that for tamoxifen to work it has to block the gene ErbB2 and it does this by using a control switch that is hidden in the background of the genome, within the ErbB2 gene itself. In order for tamoxifen to be effective, this switch must be held in the off position by Pax2. Now we understand how women can develop tamoxifen resistance.”

The production of oestrogen can cause breast cancer cells to grow and divide but tamoxifen prevents oestrogen from causing breast cancer cells to grow, helping to lower the risk of the disease returning. Most women have breast cancers that are stimulated to grow by oestrogen but not all.**

Breast cancer is the most common cancer in women in the UK. More than 45,500 women are diagnosed with the disease each year – 125 women a day, and the disease causes almost 12,500 deaths each year. Eight in 10 cases of breast cancer are diagnosed in women over the age of 50.

Professor Sir David Lane, Cancer Research UK’s chief scientist said: “Cancer Research UK’s early clinical trials of tamoxifen helped transform the way that women were treated for early breast cancer saving ten’s of thousands of lives, and this work is yet another step forward.

“More women are surviving breast cancer than ever before thanks to improvements in diagnosis and treatment as well as important fundamental science discoveries like this.”

He added: “Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women.

“Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments.”

Notes

Antoni Hurtado et al. *ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response. (2008) Nature. Wednesday 12 November.

The scientists used microarray technology (genomic technology) to define a genomic map of where oestrogen receptor interacts with the genome. The oestrogen receptor was found to interact with unexpected areas in the genome, which were then identified as the ‘switches’ for gene regulation. This provided insight into how oestrogen receptor worked. Using this information, the scientists could find the switch for the important cancer related gene, ErbB2.

Microarray technology involves scanning millions of DNA sequences to detect the association with a target sequence of DNA (in this case the regions of the genome that make contact points with the oestrogen receptor).

Breast cancer

Survival rates for breast cancer have been improving for more than twenty years and more women are being successfully treated than ever before. Nowadays more than 80 per of women diagnosed with the disease will be alive five years after diagnosis – compared with only 50 percent of women 30 years ago. This is thanks to better detection, development of new drugs and improved treatment of the disease.

Tamoxifen

**There are 45,000 new breast cancer cases in the UK each year of which about 35,000 women have oestrogen receptor (ER) positive breast cancer cells. Around 28,000 women receive tamoxifen as a first line therapy.

Tamoxifen formerly known by its brand name Nolvadex is a hormone treatment for breast cancer developed thirty years ago.

Many breast cancers are stimulated to grow by the female sex hormone oestrogen. These breast cancers are called ‘hormone sensitive’ or ‘hormone receptor positive’ and can be treated with drugs that block the effects of these hormones.

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.

University of Cambridge

As the University of Cambridge approaches its eight-hundredth anniversary in 2009, it is looking to the future. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. It admits the very best and brightest students, regardless of background, and offers one of the UK’s most generous bursary schemes.

The University of Cambridge’s reputation for excellence is known internationally and reflects the scholastic achievements of its academics and students, as well as the world-class original research carried out by its staff. Some of the most significant scientific breakthroughs occurred at the University, including the splitting of the atom, invention of the jet engine and the discoveries of stem cells, plate tectonics, pulsars and the structure of DNA. From Isaac Newton to Stephen Hawking, the University has nurtured some of history’s greatest minds and has produced more Nobel Prize winners than any other UK institution with over 80 laureates.

About the Cambridge Research Institute

The Cancer Research UK Cambridge Research Institute is a major new research centre which aims to take the scientific strengths of Cambridge to practical application for the benefit of cancer patients. The Institute is a unique partnership between the University of Cambridge and Cancer Research UK. It is housed in the Li Ka Shing Centre, a state-of-the-art research facility located on the Cambridge Biomedical Campus which was generously funded by Hutchison Whampoa Ltd, Cambridge University, Cancer Research UK, The Atlantic Philanthropies and a range of other donors. For more information visit http://www.cambridgecancer.org.uk.

About Cancer Research UK

– Together with its partners and supporters, Cancer Research UK’s vision is to beat cancer.
– Cancer Research UK carries out world-class research to improve understanding of the disease and find out how to prevent, diagnose and treat different kinds of cancer.
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