Gene that aids sense of smell play a role in spread of breast cancer to the brain

Breast cancer is the second most frequently diagnosed malignancy, just behind lung cancer, and the leading cause of cancer death in women, with more than 2 million new cases annually. Although standard therapy, consisting of surgical removal of the tumor followed by adjuvant radiation and chemotherapy, has decreased breast cancer mortality, around 12% of patients are still at high risk of relapse. Breast cancer metastasis is one of the major causes of eventual mortality; thus, novel therapeutic targets to halt or delay metastasis are of critical need.

The human olfactory receptor (OR) gene family is a crucial member of G protein-coupled receptors (GPCRs), typically expressed in the sensory neurons, and plays an essential role in various physiological processes outside the olfactory epithelium, including cancer.

ORs might play a vital role in cancer progression and metastasis. Despite these observations, the function of the OR family in breast cancer metastasis and its underlying molecular mechanisms are still largely unknown.

Now, researchers from Massachusetts General Hospital (MGH) have found that an olfactory receptor gene that aids in the sense of smell may also play a role in the metastasis of breast cancer to the brain, bones, and lungs. The team further discovered that inhibiting the gene, OR5B21 significantly decreased the metastasis of breast cancer cells to these organs and could thus be an important target for future therapy to prevent its spread, according to a paper published in iScience.

In the study, researchers established a breast cancer metastasis model by intracardiac injection of MDA-MB-231 (231P) cells in immunocompromised mice.

“The common perception is that the only role of olfactory receptors, which line the nasal cavity and relay sensory data to the brain, is to recognize odor and smell,” says Bakhos Tannous, Ph.D., director of the Experimental Therapeutics Unit in the Department of Neurology at MGH and senior author of the study. “Our work suggests that the olfactory receptor 5B21 is also a novel oncogene that may figure prominently in cancer progression by driving breast cancer cells to the brain and other sites in the body.”

“The olfactory receptor family of genes is known to be overexpressed in a variety of cancers, including prostate, melanoma, lung and liver, though its role in breast cancer has been understudied in the past,” says Litia Carvalho, Ph.D., co-corresponding author of the study and an instructor in Neurology at MGH. The team learned through its research with animal models that OR5B21 enhances or primes breast cancer cells to metastasize through a signaling pathway that activates a process known as the epithelial to mesenchymal transition (EMT). EMT prompts multiple biochemical or phenotypical changes in the olfactory cells, including the enhanced migratory capacity to distant organs, especially the brain.

“This activation converts a wide range of extracellular signals into intracellular messages through the signaling pathway NF-κB/STAT, resulting in cell proliferation, invasion and metastasis,” explains lead author Mao Li, a graduate student researcher in the Experimental Therapeutics Unit. “Our findings are novel for the field, though further research is needed to determine exactly how OR5B21 induces metastasis.”

Future research might also lead to a molecular inhibitor of OR5B21 in response to the team’s discovery that downregulating the olfactory receptor resulted in a significant decrease in cancer cell metastasis. “Our hope,” says Tannous, “is that using OR5B21 as a target for adjuvant therapy could help fill a huge unmet medical need by preventing breast cancer metastasis to the brain and other organs, and thus prolong survival of patients.”

“The role of olfactory receptors in cancer biology is gaining more attraction, and future studies may overcome this challenge with commercially available antibodies.” Study quotes.

Limitations of the study

An absence of adequate antibodies against OR5B21 limits the evaluation of OR5B21 protein expression levels in various tissues.

Researchers used Immunocompromised mice for in vivo studies. Still, since olfactory receptors have been reported to be involved in cancer immune regulation, future work needs to investigate the role of OR5B21 in an immunocompetent background to elucidate its role in anti-cancer immunity further.

The vast majority of ORs are not examined in this work and screening the olfactory receptor family expressions in primary and metastatic breast cancer.

Journal Reference

1. Mao Li, Markus W.Schweiger, Daniel J.Ryan, IchiroNakano, Litia A.Carvalho, Bakhos A.Tannous; Olfactory receptor 5B21 drives breast cancer metastasis. iScience, Volume 24, Issue 12, 17 December 2021, 103519. DOI: 10.1016/j.isci.2021.103519