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NBCF researchers are breaking down barriers in breast cancer resistance

July 27th, 2015

A research team funded through NBCF’s National Collaborative Grants Program is yielding significant results to help personalise breast cancer treatment based on the epigenetic code of a patient’s breast tumour.

In findings published this month in the prestigious journal, ”Nature Communications”, team members from Sydney’s Garvan Institute have identified how oestrogen receptor-positive breast cancers become resistant to hormone therapy and the potential of their discovery to predict patient responsiveness to hormone therapy.

Oestrogen receptor-positive breast cancer ‘feeds’ off oestrogen to grow and spread throughout the body. Current hormone therapy, such as tamofixen, blocks the cancer’s ability to connect with oestrogen, preventing this type of breast cancer.

Unfortunately, around 25% of women with oestrogen receptor-positive breast cancer who initially respond well to hormone therapies that block oestrogen eventually develop resistance to drugs, and their cancer spreads to other parts of the body.

“The mechanisms that lead to resistance are still not well understood, so we embarked on a study to see whether there was a common mechanism for endocrine resistance in oestrogen receptor-positive breast cancer,” explains the project’s Chief Investigator Professor Susan Clark.

By investigating breast cancer cells that had become resistant to different types of hormone therapy, Professor Clark and her team discovered that biochemical changes take place in the ‘oestrogen-friendly’ region on the DNA of oestrogen receptor-positive breast cancer, causing the cancer to lose its dependence on the hormone.

The biochemical changes, known as DNA ‘hypermethylation,’ mean that because the cancer is no longer dependent on oestrogen, it is no longer responsive to oestrogen-blocking hormone therapy.

Armed with this knowledge, Dr Andrew Stone, the team’s cell biologist, further analysed human breast cancer cells from patients who had done well on endocrine therapy and had not relapsed, as well as from patients who had gone on to relapse and from the same patients after they have relapsed.

He found that the oestrogen-friendly regions were ‘unmethylated’ in patients who did not relapse, ‘slightly methylated’ in patients who did go on to relapse, and heavily methylated in those patients after they relapsed.

“Our results show that the patients, who initially respond well to tamoxifen and other endocrine therapies, eventually develop resistance to drugs because of a gain of methylation of the oestrogen responsive enhancers,” said Dr Andrew Stone.

It is thought that these findings could be used to screen women with oestrogen receptor-positive breast cancer for these biochemical changes that predict how they will respond to hormone therapy – leading to a more personalised treatment plans and increased chance of survival.