Protein plays dual role in helping breast cancer tumours to grow

A protein linked to breast cancer has been found to play another, previously unknown role in enabling the disease to progress.

The discovery means that potential new drugs to target the protein, LMTK3, must take its newly discovered function into account.

It might also have implications for other forms of cancer, where similar types of proteins are being targeted for drug development.

LMTK3 belongs to a family of proteins known as kinases, which regulate other proteins inside cells – but normally only in the area of the cell outside the nucleus.

However, when the team of scientists from Imperial College London discovered LMTK3 and its role in breast cancer in 2011, they also found the protein in the cell nucleus, so decided to investigate what it was doing there.

The study, led by Dr Georgios Giamas, Professor Justin Stebbing and Dr Luca Magnani, found that LMTK3 acts in the nucleus in two different ways, both of which silence genes that would otherwise help suppress the growth of breast cancer tumours.

The findings – published in Cell Reports – could change the way that drugs are designed to target protein kinases.

"LMTK3 is found in all kinds of tissues, but it’s found at higher levels in breast cancer patients, particularly those with advanced disease," said Dr Giamas, from Imperial’s Department of Surgery and Cancer.

"We only discovered this protein four years ago and saw then that it helps breast cancer to develop and progress through its behaviour in the cytoplasm. This new research shows that what it does in the nucleus is just as important, making it a very interesting potential target to develop a treatment for the disease and stop the cancer spreading."

By studying the behaviour of the protein in breast cancer cells, the team found that LMTK3 binds to and suppresses several regions within the chromatin – the mass of DNA, RNA and proteins in the cell nucleus that enables gene transcription. They also saw that it pulls several regions of the chromatin to the edge of the nucleus, which also suppresses gene expression.

Analysis showed that the main genes affected by the action of LMTK3 in the nucleus were those that would normally reduce breast cancer tumour growth, known as tumour suppressor genes.

Using a database of breast cancer patient samples, the team also found that patients with higher levels of these genes showed better survival rates.

"The way LMTK3 behaves in the nucleus is not the normal function of a protein kinase," said co-researcher Yichen Xu, from Imperial's Department of Surgery and Cancer.

"LMTK3 is acting as a scaffold protein – basically bringing other proteins together to have this effect on the chromatin. It’s likely that other kinases might also act in a similar way, which could affect how treatments are developed that target this class of proteins."

The team are now identifying potential drugs able to block the activity of LMTK3 in both the cytoplasm and the nucleus, with the aim of developing a treatment for breast cancer.

The work was supported by organisations including Action Against Cancer, Breast Cancer Now, Cancer Research UK, the China Scholarship Council, The Jaharis Family Foundation, The Rothschild Foundation, and Euromoney plc.

Reference

 LMTK3 Represses Tumour Suppressor-Like Genes through Chromatin Remodeling in Breast Cancer, Yichen Xu, Hua Zhang, Van Thuy Mai Nguyen, Nicos Angelopoulos, Joao Nunes, Alistair Reid, Laki Buluwela, Luca Magnani, Justin Stebbing and Georgios Giamas is published in Cell Reports