A study led by Sydney’s Garvan Institute of Medical Research has revealed a new discovery regarding triple-negative breast cancers (TNBCs) - cancers which lack any of the three receptors (oestrogen, progesterone or HER2) that would make them responsive to targeted drugs.

TNBC patients typically fall into two categories: those that succumb to their disease within 3-5 years (regardless of treatment) and those that remain disease-free for longer than the average non-TNBC patient (at least eight years post-diagnosis). Garvan researchers last month published a new method that could help differentiate between the two forms of the cancer; now, a different Garvan team has said TNBCs actually comprise two distinct diseases that likely originate from different cell types.

The more aggressive form of TNBC appears to arise from stem cells, which share many of the same features as cancers - such as the ability to proliferate and spread into other tissues. The more benign form, on the other hand, appears to arise from specialised cells.

Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear. The new study, published in the journal Nature Communications, shows that a gene known as ‘inhibitor of differentiation 4’ (ID4) determines whether a stem cell remains a stem cell or differentiates into a specialist cell.

“We found that ID4 is produced at high levels in roughly half of all triple-negative breast cancers, and that these cancers have a particularly poor prognosis,” said project leader Dr Alex Swarbrick.

ID4 was also found to control the highly aggressive form of the disease, with Dr Swarbrick stating that “if you block the ID4 gene in experimental models of triple-negative breast cancer, the tumour cells stop dividing”. Furthermore, as the high levels of ID4 in a stem cell were ‘switched off’, the oestrogen receptor and other genes that drive cell specialisation were ‘switched on’.

“Oestrogen receptor-positive breast cancers have a relatively good prognosis because the drug tamoxifen is very effective at blocking the oestrogen receptor and hence their growth,” explained Dr Swarbrick.

“We speculate, therefore, that by blocking ID4 it might be possible to turn stem-cell-like breast cancers into less aggressive breast cancers that may even respond to tamoxifen. If we are correct, that would be remarkable.”

Dr Swarbrick and his team now plan to study the biochemistry of ID4 in a cell, in order to determine how best to block it in people, and to undertake therapeutic experiments in mice to test whether or not switching off ID4 sensitises a tumour to tamoxifen.