Perth researchers discover new cancer-causing gene and protein which creates highly aggressive hard to treat breast cancers.

• A novel cancer-causing gene produces large amounts of a unique protein

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• This new protein triggers tumour growth in a sub-group of hormone sensitive breast cancers
   
• Standard hormone treatments for this breast cancer fail to kill the tumour cells and may promote tumour growth and worsen survival in affected patients.

Eight years work by Harry Perkins Institute of Medical Research and The University of Western Australia’s scientist Associate Professor Pilar Blancafort, has resulted in the discovery of a cancer gene responsible for a particularly aggressive breast cancer that is typically resistant to treatment.

This research published in Nature Communications investigated hormone sensitive breast cancers, which make up about three quarters of all breast cancers, and which typically have a high survival rate.

The team discovered a previously uncharacterized group of hormone sensitive cancers that are very aggressive with poor survival in affected patients.

“Hormone sensitive breast cancers usually have better outcomes than the hormone resistant ones, such as triple negative breast cancer.

“However, a small percentage of patients experience a very aggressive cancer that results in the worst outcomes of all breast cancers, with half of all women dying from the disease”, said lead researcher Associate Professor Pilar Blancafort Cancer Epigenetics Head at Perth’s Harry Perkins Institute of Medical Research.

“When we look at these cancers, we find that they are bigger, tend to spread more commonly to lymph nodes and have a higher death rate. What we needed was to find a way to identify them and then to treat them. 

“We began by taking data from a major study in Stanford USA, looking at thousands of breast cancers. We picked those hormone driven cancers with the worst chance of survival and looked carefully at how they were different from cancers with better outcomes.

“By analysing this sub-group, we discovered these aggressive cancers have extra copies of a particular oncogene, (cancer causing gene). The cancer cells use this multiplied gene to make a cancer driving protein (AAMDC) at higher than normal levels. 

“This copying or amplification of the gene that makes the AAMDC cancer driving protein is found on a particular chromosome – chromosome 11 - in about 10% of all breast cancers. It is also present in other cancers, such as ovarian, prostate and lung cancers.

“Importantly we can now find these cancers by looking for high levels of AAMDC in the tumour cells.

“This protein is not like any other protein yet discovered, it is unique. AAMDC has a different structure or shape to all other proteins so far discovered in the human body.

“In fact, the shape or folding of the new protein most closely resembles a protein found in bacteria, rather than in human cells. Its unique shape suggests that the protein does a different job in normal human cells than all other proteins found so far.

“This protein promotes growth of the cancer, but it is unusual in that it is not under the control of estrogen and progesterone, the hormones in breast tissue which are typically the major controllers of cell growth.

“As a result this cancer protein can protect the tumour cells against anti-cancer hormone treatments, preventing the cancers from being cured.

“We discovered that the AAMDC protein can reprogram breast cancer cell metabolism, making the cells more adaptable when food and energy supplies are low. It can also activate new growth pathways in the cell which allow increasing growth and division when estrogen is removed or even when cancer cells are placed in presence of anti-estrogens.

“Usually starving hormone receptive breast cancers of estrogen causes them to shrink, but in this sub-group starving them of estrogen triggers a signal that causes the tumour to grow.

“In other words, AAMDC can protect cancer cells from dying and maintain their growth when the tumour is placed in conditions where scarcity of nutrients or starvation of estrogen growth signals would kill most hormone sensitive cancers.

“Therefore, we believe the cancer promoting function of AAMDC is to act as a ‘survival kit’, allowing tumours to adapt to these conditions supporting the growth and multiplication of breast cancer cells in conditions of metabolic stress.

“Importantly, by using new drugs which block the pathways AAMDC switches on to allow cancer cell survival, we may be able to both kill these cancer cells directly as well as restore their sensitivity to usual hormone treatments.

“Hopefully this will dramatically improve the poor outcomes these patients currently suffer.

“This is the significant discovery”, she said.

The first authors of this publication involving a multi-institutional collaboration are: Emily Golden, Rabab Rashwan and Eleanor Woodward from the Harry Perkins Institute of Medical Research.