Researchers in Australia have discovered why breast cancer treatment stops working for some patients, uncovering an unexpected role of a key cancer-fighting protein.

The study, published in Nature, found that the retinoblastoma (Rb) protein, long viewed as a natural brake on cancer growth, can unexpectedly activate genes that respond to the hormone estrogen. Some of these genes can help cancer cells withstand treatment and retain the ability to regrow, according to a statement released Thursday by Australia's Peter MacCallum Cancer Center.

The research team found that Rb does more than switch off genes that drive cell division. It can also "switch on biological programs that partially work against its own protective effects," said Peter Mac Associate Professor Shom Goel, the study's senior author.

The findings help explain why medicines known as CDK4/6 inhibitors work particularly well with endocrine therapy in hormone receptor-positive breast cancer, the most common subtype.

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

However, when cancers become resistant to endocrine therapy, the estrogen-related gene program continues despite treatment, reducing the effectiveness of CDK4/6 inhibitors, researchers found.

"Understanding this previously unknown role of Rb gives us an important new way to think about drug resistance," Goel said, adding the discovery could guide new combination therapies that keep these treatments working for longer and improve outcomes for breast cancer patients.