GPR141 regulates breast cancer progression via oncogenic mediators

Breast cancer morbidity is surging towards the peak in females across the globe. An inherent property of cancer cells is enhanced cell proliferation rate and migration capability, leading to deregulated cell signaling cascades. G-protein-coupled receptors (GPCRs) have recently emerged as a hot-spot target in cancer research.

A new research paper was published in Oncotarget's Volume 14 on May 19, 2023, entitled, “G-protein-coupled receptor 141 mediates breast cancer proliferation and metastasis by regulating oncogenic mediators and the p-mTOR/p53 axis.”

Researchers Monalisa Parija, Amit K. Adhya and Sandip K. Mishra from the Institute of Life Sciences, Regional Centre for Biotechnology and All India Institute of Medical Sciences identified aberrant expression of G-protein-coupled receptor 141 (GPR141) in different breast cancer subtypes that correlate with poor prognosis. However, the molecular mechanism via which GPR141 advances breast cancer remains elusive. Increased GPR141 expression enhances the migratory behavior of breast cancer, driving oncogenic pathways both in vitro and in vivo through activation of epithelial to mesenchymal transition (EMT), oncogenic mediators and regulation of p-mTOR/p53 signaling.

“Our study unveils a molecular mechanism for p53 downregulation and activation of p-mTOR1 and its substrates in GPR141 overexpressed cells, accelerating breast tumorigenesis.”

In their current study, the researchers found that an E3 ubiquitin ligase, Cullin1, partly mediates p53 degradation via proteasomal pathway. Co-immunoprecipitation results show that the phosphorylated form of 40S ribosome protein S6 (ps6., a p-mTOR1 substrate) forms a complex with Cullin1. These findings suggest an interplay between Cullin1 and p-mTOR1 in GPR141 overexpressed cells that downregulates p53 expression, thus inducing tumor growth.

GPR141 silencing restores p53 expression and attenuates p-mTOR1 signaling events, thereby impeding proliferation and migration in breast cancer cells. Their findings describe the role of GPR141 in breast cancer proliferation, and metastasis, as well as in influencing the tumor microenvironment. Modulating GPR141 expression could pave the way for a better therapeutic approach to regulating breast cancer progression and metastasis.

“In conclusion, our research highlights the gain of function of GPR141 drives breast tumorigenesis by inducing tumor cell properties via the p-mTOR1/p53 axis, altering EMT markers, and enhancing oncogenic mediators.”

Ref:G-protein-coupled receptor 141 mediates breast cancer proliferation and metastasis by regulating oncogenic mediators and the p-mTOR/p53 axis,Oncotarget,DOI10.18632/oncotarget.28433

NEWS RELEASE 22-MAY-2023

Promising skin patch for toddlers with peanut allergy

Peanut allergy affects approximately 2 percent of children in the United States, Canada and other westernized countries, and it commonly persists into adulthood. Life-threatening allergic reactions can be triggered by unintentional exposure to minute quantities, including through products manufactured on shared equipment as peanuts. Currently, there are no approved treatments for peanut-allergic children younger than 4 years of age.

A global phase 3 clinical trial that included Ann & Robert H. Lurie Children’s Hospital of Chicago found that a year-long immunotherapy through a skin patch safely desensitized toddlers with peanut allergy, lowering the risk of a severe allergic reaction from accidental exposure. Results of this randomized, double-blind, placebo-controlled trial for children 1-3 years of age, funded by DBV Technologies, were published in the New England Journal of Medicine.

“We were excited to contribute to this landmark study that carries so much promise for our young patients with peanut allergy,” said co-author Melanie Makhija, MD, who was the Principal Investigator of the study at Lurie Children’s and is an Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “Children who originally reacted to a small fraction of a peanut were able to tolerate the equivalent of one to four peanuts after completing the treatment course. This means that these children will be well protected from accidental exposure to peanuts. Importantly, we found that the peanut patch was safe, with very low chances of a severe allergic reaction. This is terrific news for families of kids with peanut allergies.”

Since 2012, the clinical trials program for food allergies at Lurie Children’s has enrolled patients on numerous studies of novel treatments, including the oral immunotherapy for peanuts that has been approved by the Food and Drug Administration (FDA). Ongoing trials are available for all age groups, from infancy to young adulthood.

Reference:

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy,New England Journal of Medicine,https://www.nejm.org/doi/10.1056/NEJMoa2212895