News release

From: Peter MacCallum Cancer Centre

Researchers at Peter Mac have discovered why breast cancer treatment stops working for some patients, uncovering the unexpected role of one of the body's most important cancer-fighting proteins.

The study, published in Nature, revealed that the retinoblastoma (Rb) protein - long considered one of the body's natural brakes on cancer growth - has a more complex function than previously understood.

Rb normally works by preventing cells from dividing uncontrollably, helping to protect against cancer. In hormone receptor-positive (HR+) breast cancer, the most common subtype of breast cancer, medicines known as CDK4/6 inhibitors switch Rb back on, slowing tumour growth. These drugs have transformed treatment for many patients, but most cancers eventually become resistant.

The research team, led by Associate Professor Shom Goel alongside Postdoctoral Research Fellows Dr April Watt and Dr Antonio Ahn, determined that Rb does more than switch off genes that drive cell division. It can also switch some genes on.

The researchers found that it unexpectedly activates a group of genes that respond to the hormone oestrogen. Some of these genes can help cancer cells withstand treatment and retain the capacity to begin growing again.

"We've always viewed Rb as a straightforward tumour suppressor that puts the brakes on cancer cell growth," Associate Professor Shom Goel said.

"Our study shows that the story is far more nuanced. While Rb continues to block cell division, it can also switch on biological programs that partially work against its own protective effects."

The discovery also helps explain why CDK4/6 inhibitors and endocrine therapy work so well together.

“These treatments complement each other remarkably well," Associate Professor Goel said.

"The CDK4/6 inhibitor activates Rb to stop cancer cells dividing, while endocrine therapy blocks the unwanted oestrogen-driven signals that Rb can also trigger. Together, they allow the tumour-suppressing effects of Rb to dominate."

However, the researchers found that this balance changes when cancers become resistant to endocrine therapy. In these tumours, the oestrogen-related gene program continues despite treatment, reducing the effectiveness of CDK4/6 inhibitors.

"Understanding this previously unknown role of Rb gives us an important new way to think about drug resistance," Associate Professor Goel said.

"We hope these insights will guide the development of new combination therapies that keep these treatments working for longer and ultimately improve outcomes for people with breast cancer.”

“This work also changes how we think about tumour suppressors more broadly,” he said.

“We tend to divide cancer proteins into good actors and bad actors. But our findings show that even a protein whose main role is to prevent cancer can have other effects that help tumour cells adapt to treatment.”

“That opens up a new way of understanding how tumour suppressors work, and how we might target their less helpful effects without losing their protective activity.”

This research was funded by Snow Medical, The Mark Foundation, and the Breast Cancer Research Foundation.