Receptor Dimerization Linked to Breast Cancer Growth, Potential New Treatment Target Identified
Breast cancer’s ability to grow and spread often depends on complex molecular interactions that scientists are still working to understand. Researchers have identified a mechanism involving the receptor VIPR2, which can bind to itself and form dimers that promote tumor growth and metastasis.
A receptor involved in normal physiological processes may also drive breast cancer growth when overexpressed. Scientists at Hiroshima University have identified a mechanism involving the receptor VIPR2, and their work suggests that small chains of protein building blocks could potentially be developed into a new type of anticancer treatment.
Understanding VIPR2 and its Role in Breast Cancer
The research, published in the British Journal of Pharmacology, centers on vasoactive intestinal peptide receptor-2 (VIPR2). Under normal conditions, VIPR2 regulates circadian rhythm, immune responses, and insulin release, among other biological processes.
Problems arise when VIPR2 is overexpressed, leading to faster breast cancer cell growth and the spread of the disease. When present at high levels, the receptor can attach to another copy of itself, forming a structure called a dimer.
How Receptor Dimerization Fuels Tumor Progression
According to co-corresponding author Satoshi Asano, assistant professor in the Department of Cellular and Molecular Pharmacology at Hiroshima University’s Graduate School of Biomedical and Health Sciences, many protein receptors can form pairs with identical molecules in a process called homodimerization. When two receptors combine, the resulting dimer can behave differently than a single receptor unit (a monomer).
“However, it was unclear whether VIPR2 monomers directly interact with each other and what function the dimeric receptor has in breast cancer cells,” Asano said.
Researchers confirmed that VIPR2 molecules directly connect to form homodimers. They then used cell-based experiments and a mouse model to examine the influence of these receptor pairs on cancer.
Their results showed that dimerized VIPR2 contributes to breast tumor growth and metastasis through the interaction at the transmembrane domains (TM) 3 and 4. These regions can either strengthen the pairing between two VIPR2 molecules or prevent it from forming.
Targeting Dimerization with TM3-4 Peptides
The presence of small chains of amino acids called TM3-4 peptides influences whether the receptors remain paired. These peptides interfere with the interaction between the transmembrane domains.
“We found that VIPR2 moved further apart in cells expressing TM3-4-peptides, suggesting that TM3-4 prevents VIPR2 dimerization,” Asano said. “Breast cancer cells stably expressing TM3-4 region exhibited suppressed tumor growth and lymph-node metastasis.”
This process of breaking apart dimers is called de-dimerization.
“VIPR2 de-dimerized by expression of TM3-4 had reduced affinity for specific proteins and was no longer involved in the activation of signaling pathways involved in cell proliferation and metastasis,” said co-corresponding author Yukio Ago, professor in the Department of Cellular and Molecular Pharmacology at Hiroshima University’s Graduate School of Biomedical and Health Sciences.
Future Directions: Developing Novel Anticancer Drugs
Researchers plan to verify the anticancer effect of the purified TM3-4 peptide in animal models. Their goal is to develop new anticancer drugs that target cancer cells where dimerization is enhanced due to increased VIPR2 expression.
This research was supported by the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, the Hiroshima University Fund “Nozomi H Foundation” and the Tokyo Biochemical Research Foundation.