Triple negative breast cancer (TNBC) represents approximately 15% of the newly diagnosed cancers worldwide and is characterized by tissue lacking in estrogen, progesterone and human epidermal growth factor receptors. TNBC disproportionately affects younger women and women of colour, and new treatments are needed. The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a determinant of cell proliferation in neoplasia, and OGF is an endogenously produced pentapeptide that inhibits cell replication by interacting with OGFr and upregulating cyclin-dependent inhibitory kinase pathways thus reducing DNA synthesis. In these studies we investigated the presence and function of the OGF-OGFr axis in two human TNBC cell lines, as well as in breast cancer cell lines containing hormonal receptors. TNBC cell lines MDA-MD-231 and BT-20, as well as human breast cancer cells SK-BR-3 and MCF-7, were examined for the presence of pentapeptide and receptors, as well as their response to OGF. Specificity of peptide and receptor was confirmed by antibody neutralization and molecular studies to knockdown classical receptor protein. The requirement for protein transcription and translation and RNA transcription were investigated. Growth of TNBC cells in the presence of OGF and standard of care chemotherapeutic agent paclitaxel was evaluated to determine both efficacy and protective effects against toxicity. OGF treatment inhibited TNBC cells in a dosage related, receptor mediated, and reversible manner. OGF was the specific endogenous opioid to inhibit cell proliferation, and this was mediated by p21 cyclin dependent inhibitory kinase pathways, and required protein and RNA synthesis. OGFr was the specific receptor involved; both peptide and receptor were detected in all four cell lines. OGF treatment inhibited growth of all cancer cell lines evaluated, and reduced cell death in cultures exposed to paclitaxel. The OGF-OGFr axis is present and functioning in TNBC cell lines, and provides a novel biological pathway as potential therapy.
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.
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