Researchers have identified a molecular biomarker in triple-negative breast cancers that may inform when beta blockers can play a role in “switching off” tumor progression. These findings were published by Lam et al in Science Signaling.
When stress hormones are released by the body’s nervous system, they can activate the β2-adrenoceptor, which can speed up the spread of cancer. Beta blockers are a class of medication used to block the effects of stress hormones and have already been identified as a potential therapeutic option for halting disease progression in patients with triple-negative breast cancer. The team behind the new research has now discovered how beta blockers may play a role in stopping progression of triple-negative breast cancer in some patients, paving the way for better informed beta blocker prescribing at the time of diagnosis.
They identified that the interplay between two cell signals—cAMP and calcium—may trigger cancer progression when the β2-adrenoceptor is active and that the HOXC12 gene is central to “switching on and off” this interplay. Using the gene-editing tool CRISPR-Cas9, the researchers deleted HOXC12, which stopped the β2-adrenoceptor–cAMP–calcium interplay.
Senior author Michelle Halls, PhD, of the Monash Institute of Pharmaceutical Sciences (MIPS), explained that the discovery is exciting because there has been mounting evidence indicating a strong link between beta blockers preventing metastasis in some patients with triple-negative breast cancer; however, until now, investigators didn’t know why this is the case.
“Our colleagues at MIPS, who were also pivotal to this latest study, had previously found that beta blockers are associated with a significant reduction in mortality in people with triple-negative breast cancer,” said Dr. Halls. “Now we have a much better grasp on why this could be the case. In [our new study], we looked at several triple-negative breast cancer cell types and found that one gene in particular, HOXC12, is a key mediator of the β2-adrenoceptor–cAMP–calcium ‘feedforward loop’ in triple-negative breast cancer. This information means that if HOXC12 is found to be present in patients with triple-negative breast cancer, they could be ideal candidates for beta blocker therapy.”
Terrance Lam, the first author of the study and a MIPS PhD candidate, said the team further validated its findings through analysis of a comprehensive patient genomic database. “The patient analysis showed that high levels of HOXC12 expression in patients with triple-negative breast cancer was associated with poorer overall survival. Taking this into account, our collective research strongly suggests that HOXC12 is a potential new indicator for when triple-negative breast cancer patients could respond to beta blocker targeted interventions,” Mr. Lam said.
“Ultimately, this exciting discovery could pave the way to improving survival outcomes in people with triple-negative breast cancer when HOXC12 is found to be present. We believe further studies are urgently needed to determine if HOXC12 can be used to identify patients who will benefit from beta blocker therapy at the time of diagnosis and stop tumor spread, thus increasing survival rates,” he concluded.
Disclosure: For full disclosures of the study authors, visit science.org.
