Opioid growth factor receptor (OGFR) expression is downregulated with progression of triple negative breast cancer

Beth Worley,Patricia Mclaughlin,Ian Zagon

doi:10.14319/ijcto.34.7

Beth Worley, Patricia Mclaughlin + Show 1 more

Open Access

https://doi.org/10.14319/ijcto.34.7

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Abstract

Purpose: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that accounts for approximately 15% of the newly diagnosed cancers worldwide, and disproportionately affects younger women and women of color. Although many forms of breast cancer are successfully treated, new therapies are needed for TNBC. A novel regulatory system, the opioid growth factor (OGF) – opioid growth factor receptor (OGFr) axis, plays a determining role in neoplasia. OGF is an endogenous peptide that binds specifically to OGFr to inhibit cell replication. As some human cancers grow, OGFr expression is diminished, thus limiting the therapeutic efficacy of OGF. The OGF-OGFr axis is present in human TNBC cell line MDA-MB-231 and OGF inhibits cell replication in a dosage-related, receptor-mediated manner. Methods: The present study investigated whether OGFr protein expression in human breast cancer cell lines grown in vitro or transplanted into nude mice, changed with the stage of proliferation or size of tumor using western blotting, semi-quantitative immunohistochemistry, and DNA synthesis techniques. Results: Comparison of log and confluent TNBC cultures revealed that OGF expression was significantly decreased in confluent cultures relative to levels in log-phase cells. Western blot analyses confirmed that OGFr was reduced in confluent TNBC and MCF-7 breast cancer cells in comparison to corresponding log-phase cells. Moreover, BrdU labeling was reduced in confluent cells. Small ( 1000 mm 3 ) TNBC tumors grown in nude mice were processed for semiquantitative measurement of OGF and OGFr. The expression of both peptide and receptor in large tumors was downregulated relative to small tumors. Conclusion : The reduced expression of the inhibitory peptide and receptor diminishes the efficacy of the OGF-OGFr axis as a biotherapy. These data suggest that the OGF-OGFr pathway is altered with cancer progression and one or more elements of this regulatory pathway may serve as biomarkers for TNBC growth.

Highlights

The opioid growth factor (OGF) – OGF receptor (OGFr) pathway is present in a wide variety of cancers,[11] including Triple negative breast cancer (TNBC), and has been shown to modulate neoplasias related to the female reproductive system.[12,13,14,15,16]
The present study examined the hypothesis that progression of TNBC may be associated with a decrease in OGFr protein rendering the tumor tissue less responsive to endogenous or exogenous OGF treatment
MDA-MB-231 TNBC cells grown to either log phase or confluency were stained with OGF and OGFr antibodies (Figure 1A)

Summary

Introduction

Triple negative breast cancer (TNBC) constitutes less than 20% of all cases of invasive breast cancer, but remains the most aggressive form of breast cancer.[1,2] TNBC does not express the three hormonal receptors estrogen (ER), progesterone (PR), and human epidermal growth factor (HER2) that serve as targets for chemotherapy and immunotherapy for other breast cancers,[3,4] making it resistant to many of the viable treatment options available for breast cancer therapy.[2,5,6,7] The prognosis for successful treatment and extended survival for women with ER, PR, and/or HER2 detected in breast tissue approaches 98%,2 whereas the median survival time for patients with TNBC is 13 months.[2,7] TNBC has an increased prevalence in younger females, women of color, and those from lower socioeconomic countries.[2]. Other kinases such as p15 and p18 were not affected by OGF

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