Growth of Triple Negative Human Breast Cancer Cells is Regulated by the OGF‐OGFr Axis

Abstract

Breast cancer is the most common cancer, and the leading cause of cancer death, in females worldwide. Triple negative breast cancer (TNBC) accounts for 10–20% of all breast cancers. There are no targeted therapies for TNBC. The opioid growth factor (OGF) and its receptor (OGFr) is a tonically active inhibitory pathway that regulates normal and neoplastic cell proliferation, and we hypothesize that the OGF‐OGFr axis is a determinant of the progression of TNBC. Both OGF and OGFr were detected in TNBC human cell line MDA‐MB‐231 by immunohistochemistry. Receptor binding assays revealed specific and saturable binding (Bmax = 8.5 ± 1.8 fmol/mg protein; Kd = 4.1 ± 1.1 nM). Exogenous OGF depressed growth by 19 to 28% beginning at 24 hr and persisting to 120 hr. Growth inhibition was dose‐dependent (10−4M to 10−10 M), reversible, and receptor‐mediated, and suppression of cell proliferation was dependent on RNA and protein synthesis. Other endogenous and synthetic opioids, including those targeting μ, δ, and κ opioid receptors, did not alter growth at a concentration of 10−6 M. Cells with a knockdown of OGFr using siRNA did not respond to OGF. A complete blockade of the OGF‐OGFr axis with the opioid antagonist naltrexone increased cell number, indicating that this peptide‐receptor complex is critical in maintaining homeostasis of cell proliferation. These data show that the OGF‐OGFr system is present and functioning as a native biological regulator of human breast cancer, and will be important in designing treatment strategies for this group of deadly neoplasias. Supported by the Paul K. and Anna E. Shockey Family Foundation.