Hypoxia-Induced NPY1R And NPY5R Are Linked To Breast Cancer Progression And Can Be Antagonized With Commercially Available Inhibitors

Abstract

Neuropeptide Y (NPY) is the most abundant neuropeptide in the mammalian central and peripheral nervous system. It acts on the cardiovascular, digestive, immune, endocrine, nervous, and immune systems. Various NPY receptors (NPYRs) display elevated expression in different types of cancers, but NPY1R and NPY5R are the most highly expressed in breast tumours. Here, we investigate how hypoxia, a feature that drives malignancy in the tumour microenvironment, influences the activity of NPYRs. We show that NPY1R and NPY5R expression and activity are directly influenced by hypoxia inducible factors (HIFs) in both ER+ (MCF7) and ER- (MDA-MB-231) cell lines. We found that cells are more responsive to NPY5R stimulation in hypoxia compared to normoxia, leading to enhanced migration and proliferation. We demonstrate that we can impede these augmented responses through pharmacological inhibition of NPY1R in MDA-MB-231 and NPY5R in MCF7. We establish that these cellular responses occur in both cell monolayers and spheroids, which recapitulate the tumour microenvironment more closely. In line with this, we find that expression of NPY1R and NPY5R correlate with adverse patient outcomes in breast tissue samples from the Ontario Tumour Bank. This study reveals for the first time that hypoxia-induced NPYRs render cells more sensitive to NPY stimulation, and that this response can be impeded by blocking the receptors. Since breast tissue is highly innervated by the nervous system, and the expression of NPYRs correlate with negative patient prognosis, further research into antagonizing these receptors may aid in the development of novel therapeutics and personalized treatment plans.