SRC-3 Elimination Triggers Long-Lasting Anti-Cancer Response

Baylor College of Medicine researchers have uncovered a critical regulator of the anti-cancer immune response, which could shift the game in the fight against cancer. The study, which was published in the Proceedings of the National Academy of Sciences, found that in animal models of breast and prostate cancer, removing the gene SRC-3, specifically in a type of immune cell called regulatory T cells (Tregs), triggered a lifelong anti-cancer response that eradicated the tumor without the typical side effects seen with other therapies.

Furthermore, introducing Tregs lacking SRC-3 to animals carrying breast cancer tumors resulted in long-term tumor eradication with no harmful side effects. The findings urge future research to establish the efficacy of this strategy in treating human disease.

“More than 30 years ago, my lab discovered a protein we called 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 and cellular biology at Baylor. “Since then, we have discovered that a family of SRCs (SRC-1, SRC-2 and SR-3), regulates the activity of a variety of cellular functions.”

The O’Malley lab and colleagues have been particularly interested in SRC-3 and its role in cancer over the years. SRC-3 is not only found in all human tumors and plays a role in cancer progression, but it is also found in Tregs, which govern the immunological response to cancer. O’Malley and his colleagues explored the effect of deleting the gene SRC-3 in Tregs on breast cancer growth because they were intrigued by the prevalence of SRC-3 in Tregs and suspected that it might play a role in limiting cancer progression.

The researchers created animals lacking the SRC-3 gene only in Tregs (SRC-3 knock-out) and then compared the progression of breast cancer in these mice to the progression of breast cancer in mice with the SRC-3 gene.

“We were surprised by the results,” O’Malley said. “Breast tumors were eradicated in the SRC-3 knock-outs. A subsequent injection of additional cancer cells in these mice did not give rise to new tumors, showing that there was no need to generate additional SRC-3 knock-outs to sustain tumor resistance. Importantly, transferring these cells to animals carrying pre-established breast tumors also resulted in anti-cancer response. We obtained similar results with prostate cancer.”

The researchers also discovered that Tregs missing SRC-3 enabled long-term tumor eradication by efficiently altering the environment surrounding the tumor to favor its removal.

O’Malley and his colleagues showed, using a variety of laboratory techniques, that the modified Tregs proliferated widely and preferentially penetrated breast tumors, where they produced chemicals that elicited an anti-tumor immune response. On the one hand, the chemicals aided the entry of immune cells—T cells and natural killer cells—that directly targeted the tumor, while on the other hand, changed Tregs prevented other immune cells that attempted to thwart the anti-tumor response.

“Other published treatments seem to reduce tumor burden or eliminate the cancer for some time, but in most cases it returns. Our findings in animal models are the first to show that Tregs lacking SRC-3 eradicate established cancer tumors and appear to confer long-lasting protection against recurrence,” said first author Dr. Sang Jun Han, associate professor of molecular and cellular biology and in the Center for Reproductive Medicine at Baylor. He also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “We are very excited about the results; altogether they warrant continuing our investigations to translate the findings into a novel, more effective and longer-lasting cancer therapy.”

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