When doctors diagnosed Linda with the most common type of breast cancer, she was relieved to learn there was a drug that could help. The treatment worked for years. Then it stopped. Now, scientists in Melbourne believe they finally understand why — and what they found surprised everyone.
Researchers at Peter MacCallum Cancer Centre discovered that one of the body's most important cancer-fighting proteins has a hidden double life. The protein, called retinoblastoma or Rb, has been considered a straightforward hero in the fight against cancer for decades. But new research published in Nature reveals it may also help tumors survive treatment.
Rb normally acts like an emergency brake in our cells, stopping them from dividing out of control and becoming cancer. In hormone receptor-positive breast cancer — the most common subtype, affecting about 70 percent of breast cancer patients — doctors use drugs called CDK4/6 inhibitors to switch Rb back on. These medicines have transformed treatment for many people. But for most patients, the cancer eventually finds a way to resist the drugs and starts growing again.
The research team, led by Associate Professor Shom Goel alongside postdoctoral fellows Dr. April Watt and Dr. Antonio Ahn, made a startling discovery. While Rb does block the genes that cause cancer cells to divide, it also unexpectedly turns on a separate set of genes that respond to the hormone estrogen. Some of these genes can help cancer cells withstand treatment and recover their ability to grow.
"We've always viewed Rb as a straightforward tumor suppressor that puts the brakes on cancer cell growth," Goel said. "Our study shows that the story is far more nuanced."
The finding also explains why two different treatments work better together. CDK4/6 inhibitors activate Rb to halt cell division, while a separate therapy called endocrine therapy blocks the estrogen signals that Rb can also trigger. When used as a pair, the tumor-fighting effects of Rb take over completely.
The problem arises when cancer becomes resistant to endocrine therapy. In these cases, the estrogen-related genes keep working despite treatment, weakening the effect of CDK4/6 inhibitors and allowing tumors to resume growing.
Understanding this hidden role of Rb gives researchers a new way to think about drug resistance. The team hopes their findings will help scientists design better combination therapies that keep these medicines working longer and improve outcomes for breast cancer patients.
Goel noted that the discovery changes how we should view tumor-suppressing proteins in general. "We tend to divide cancer proteins into good actors and bad actors," he said. "But our findings show that even a protein whose main role is to prevent cancer can have other effects that help tumor cells adapt to treatment."
That insight opens a new research path: targeting the less helpful effects of cancer-fighting proteins without losing their protective power.