SRC-3 gene: Deletion in immune cells activates an anti-cancer response

Transfer of SRC-3-free Tregs to animals bearing breast tumors also resulted in long-term tumor elimination without adverse side effects. The results encourage further investigations to determine the value of this approach for the treatment of human disease.

“More than 30 years ago, my lab discovered a protein we called the steroid receptor coactivator (SRC) that is required for the effective regulation of gene activity,” said corresponding author Dr. Bert W. O’Malley, chancellor and professor of molecular biology and cell biology at Baylor. “Since then, we have discovered that a family of SRCs (SRC-1, SRC-2 and SR-3) regulate the activity of a variety of cellular functions.”

Over the years, O’Malley’s lab and colleagues have taken a particular interest in SRC-3 and its role in cancer. SRC-3 is not only highly expressed in all human cancers and plays a role in cancer growth, it is also strongly expressed in Tregs that regulate the immune response to cancer.

Intrigued by the abundance of SRC-3 in Tregs and suspecting that it might play a role in controlling cancer progression, O’Malley and his colleagues investigated the effect of deleting the SRC-3 gene in Tregs on cancer growth at the breast.

The team generated mice lacking the SRC-3 gene in Tregs only (SRC-3 knock-out) and then compared the progression of breast cancer in these mice to the progression in mice that had the SRC-3 gene.

“We were surprised by the results,” O’Malley said. “Breast cancers have been eradicated in SRC-3 knockouts. Subsequent injection of additional tumor cells into these mice did not give rise to new tumors, demonstrating that it was not necessary to generate additional SRC-3 knockouts to sustain tumor resistance. Importantly, the transfer of these cells to animals bearing pre-established breast tumors has also led to the eradication of the cancer. We’ve had similar results with prostate cancer.”

The team also found that SRC-3-deficient Tregs mediated long-lasting tumor eradication by effectively changing the environment surrounding the tumor to one that was conducive to tumor elimination.

Using a variety of laboratory techniques, O’Malley and his colleagues found that the modified Tregs proliferated extensively and preferentially infiltrated breast tumors where they released compounds that engendered an antitumor immune response. On the one hand, the compounds facilitated the entry of immune cells – T cells and natural killer cells – which directly attacked the tumor and, on the other hand, the modified Tregs blocked other immune cells attempting to stop the anti-tumor response.

“Other published treatments appear to reduce tumor burden or eliminate the cancer for some time, but in most cases it comes back. Our results in animal models are the first to demonstrate that SRC-3-deficient Tregs eradicate established cancer tumors and appear to confer long-lasting protection against recurrence,” said first author Dr. Sang Jun Han, associate professor in molecular and cell biology and at the Center for Reproductive Medicine at Baylor.

He is also a fellow of the Dan L Duncan Comprehensive Cancer Center at Baylor. “We are very excited about the results; taken together, they justify the continuation of our investigations to translate the findings into a new, more effective and longer-lasting cancer therapy.”