Study uncovers how beta blockers could halt the progression of triple negative breast cancer

Monash University researchers have identified a molecular biomarker in triple negative breast cancer (TNBC) tumors which could inform when beta blockers can play a role in “switching off” tumor progression.

When stress hormones are released by the body’s nervous system, they can activate a receptor called the “beta-2adrenoceptor,” 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 by Monash researchers as a potential therapeutic option for halting cancer progression in TNBC patients.

A Monash Institute of Pharmaceutical Sciences (MIPS) team has now discovered how beta blockers could play a role in stopping TNBC progression in some patients, paving the way for better informed beta blocker prescribing at the time of diagnosis.

The Science Signaling study has identified that the interplay between two cell signals, “cAMP” and “calcium,” can trigger cancer progression when the β2-adrenoceptor is active and that a gene called HOXC12 is central to switching this interplay on and off.

Using gene-editing tool CRISPR-Cas9, the researchers deleted HOXC12, which stopped the β2-adrenoceptor-cAMP-calcium interplay. This discovery shows that HOXC12 could be the key to identifying patients who will benefit from beta blocker therapy at the time of diagnosis.

Senior author, Associate Professor Michelle Halls from MIPS, said the discovery is exciting because there has been mounting evidence indicating a strong link between beta blockers preventing metastasis in some TNBC patients; however, until now, they didn’t know why this is the case.

“Our colleagues at MIPS, who were also pivotal to this latest study, have previously found that beta blockers are associated with a significant reduction in mortality in people with TNBC,” Associate Professor Halls said.

“Now we have a much better grasp on why this could be the case. In the Science Signaling study we looked at several TNBC cancer cell types and found that one gene in particular, HOXC12, is a key mediator of the β2-adrenoceptor-cAMP-calcium ‘feedforward loop’ in TNBC. This information means that if HOXC12 is found to be present in a TNBC patient, they could be an ideal candidate for beta blocker therapy.”

Terrance Lam, the first author and MIPS Ph.D. candidate, said the team further validated their findings through analysis of a comprehensive patient genomic database.

“The patient analysis showed that high levels of HOXC12 expression in patients with TNBC 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 TNBC when HOXC12 is found to be present. TNBC is an aggressive cancer which can be especially challenging to treat and identifying new treatment pathways are important—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.”

Monash University researchers have identified a molecular biomarker in triple negative breast cancer (TNBC) tumors which could inform when beta blockers can play a role in “switching off” tumor progression.

When stress hormones are released by the body’s nervous system, they can activate a receptor called the “beta-2adrenoceptor,” 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 by Monash researchers as a potential therapeutic option for halting cancer progression in TNBC patients.

A Monash Institute of Pharmaceutical Sciences (MIPS) team has now discovered how beta blockers could play a role in stopping TNBC progression in some patients, paving the way for better informed beta blocker prescribing at the time of diagnosis.

The Science Signaling study has identified that the interplay between two cell signals, “cAMP” and “calcium,” can trigger cancer progression when the β2-adrenoceptor is active and that a gene called HOXC12 is central to switching this interplay on and off.

Using gene-editing tool CRISPR-Cas9, the researchers deleted HOXC12, which stopped the β2-adrenoceptor-cAMP-calcium interplay. This discovery shows that HOXC12 could be the key to identifying patients who will benefit from beta blocker therapy at the time of diagnosis.

Senior author, Associate Professor Michelle Halls from MIPS, said the discovery is exciting because there has been mounting evidence indicating a strong link between beta blockers preventing metastasis in some TNBC patients; however, until now, they didn’t know why this is the case.

“Our colleagues at MIPS, who were also pivotal to this latest study, have previously found that beta blockers are associated with a significant reduction in mortality in people with TNBC,” Associate Professor Halls said.

“Now we have a much better grasp on why this could be the case. In the Science Signaling study we looked at several TNBC cancer cell types and found that one gene in particular, HOXC12, is a key mediator of the β2-adrenoceptor-cAMP-calcium ‘feedforward loop’ in TNBC. This information means that if HOXC12 is found to be present in a TNBC patient, they could be an ideal candidate for beta blocker therapy.”

Terrance Lam, the first author and MIPS Ph.D. candidate, said the team further validated their findings through analysis of a comprehensive patient genomic database.

“The patient analysis showed that high levels of HOXC12 expression in patients with TNBC 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 TNBC when HOXC12 is found to be present. TNBC is an aggressive cancer which can be especially challenging to treat and identifying new treatment pathways are important—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.”