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Three of the most important discoveries in breast cancer research

Over the past 40 years there have been some ground-breaking discoveries in breast cancer research. For many of these, the journey is one that spans decades, beginning with scientists trying to understand the basic biology of human cells in the lab, and finishing with a plethora of clinical trials and health policy debates that have transformed how doctors treat breast cancer. In this blog we take a brief look at three of the biggest discoveries. All of these started with a bright idea in a lab and countless hours of research before they reached the clinic. Worldwide Cancer Research are proud to support this early-stage research, which is why we have invested nearly £200m to help kick-start the next big discovery.

#1 - Oestrogen receptors

Oestrogen receptors (ER for short) were first identified in cells back in 1958. It was subsequently discovered that these receptors sit in the outer membrane of cells and soak up the hormone oestrogen. This stimulates the cells to grow and divide, so it’s no surprise that over 70 percent of breast cancers are made of cells that have more oestrogen receptors than they should. Scientists call this type of breast cancer ER-positive.

The fact that ER-positive breast cancers are identifiable by this characteristic allowed scientists to develop ways to use oestrogen receptors as a target for treatment. Fast forward to 1970 and the first clinical trial in breast cancer for a drug that exploits this feature of cancer cells was carried out in Manchester. The drug, called tamoxifen, is still used today as a primary treatment option for patients with ER-positive breast cancer. Tamoxifen is so important that the World Health Organisation placed it on their List of Essential Medicines.

Unfortunately, many people who initially respond well to tamoxifen eventually become resistant to the drug, so the next challenge is to understand how this occurs so it can be circumvented. Professor Clare Isacke at the Institute of Cancer Research in London used funding from Worldwide Cancer Research to understand how a protein called RET might be involved in this process. Her teams work revealed that RET might be an important therapeutic target for ER-positive cancers that are resistant to tamoxifen.

#2 - BRCA genes

BRCA are probably the most well-known cancer genes thanks to the Angelina Jolie’s 2013 letter in the New York Times explaining why she chose to have a double mastectomy to reduce her risk of breast cancer. Jolie carries a mutated form of the gene BRCA1, which, on average, increases lifetime risk of breast cancer by 65 percent. Identification of these genetic mutations and their association with breast cancer risk had a significant impact on the prevention, diagnosis and treatment of the disease.

Knowing the faulty versions of BRCA genes allows us to use genetic testing to identify at-risk people so they can be advised on things they can do to manage their risk. This might be preventative surgery, like in the case of Angelina Jolie, changes in lifestyle, or even just extra monitoring so that early signs of cancer are detected.

Pioneering research that uncovered the role of BRCA genes in normal cells led to the discovery that cancer cells carrying a faulty version were particularly sensitive to a type of drug, called a PARP inhibitor, which targets the cells ability to repair damaged DNA. One PARP inhibitor, called olaparib, is currently approved to treat people with a particular type of ovarian cancer, and clinical trials are ongoing in breast, stomach and pancreatic cancer.

In the mid-1990s Worldwide Cancer Research gave grants to Professor Steve Jackson in Cambridge for a series of projects studying DNA repair. He used findings from these projects, along with others, to set up a company called KuDOS Pharmaceuticals Ltd. KuDOS went on to develop olaparib.

#3 - HER2 and trastuzumab

In the 1980s researchers discovered a gene called ERBB2 which turned out to be the instructions cells use to produce a protein called HER2. The link between HER2 and cancer was uncovered in later years when it was found that tumour cells with excessively high levels of HER2 were present in 25 to 30 per cent of all breast cancer cases. Researchers called these HER-2 positive breast cancers.

HER2 tells cells to grow and divide so it was proposed that blocking the protein might be a good way to target cancer cells and stop tumours growing. Using this concept, researchers developed antibodies – natural biological molecules that can stick to proteins – that could seek out HER2 and stop it from working. Tests in the lab, and then in mice, showed that these antibodies were very effective at slowing down the growth of HER2-positive tumours. This work led to the development of the antibody trastuzumab (also called Herceptin), which in 1998 finished clinical trials with remarkable results. Like tamoxifen, trastuzumab is now on the World Health Organisation’s List of Essential Medicines.

As with many cancer therapies, the development of resistance to trastuzumab is a problem that researchers are working hard to tackle. Worldwide Cancer Research is currently funding Professor Miguel Lopez-Botet in Barcelona, who is trying to find clever ways to give the immune system a helping hand so that trastuzumab works more effectively.

Top image credit: National Cancer Institute

Science Communications Manager

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