Ghrelin expression is associated with a favorable outcome in male breast cancer

Malin Grönberg,Carl Blomqvist,Cecilia Nilsson,Ingrid Hedenfalk,Lars Holmberg,Eva Tiensuu Janson,Ida Markholm,Marie-Louise Fjällskog

doi:10.1038/s41598-018-31783-x

Abstract

Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clinical implications of the peptide expression in male breast cancer are unclear. The aim of this study was to investigate the role and potential clinical value of ghrelin and obestatin in male breast cancer. A tissue microarray of invasive male breast cancer specimens from 197 patients was immunostained with antibodies versus the two peptides. The expression of the peptides was correlated to previously known prognostic factors in breast cancer and to the outcome. No strong correlations were found between ghrelin or obestatin expression and other known prognostic factors. Only ghrelin expression was statistically significantly correlated to breast cancer-specific survival (HR 0.39, 95% CI 0.18–0.83) in univariate analyses and in multivariate models, adjusted for tumor size and node status (HR 0.38, 95% CI 0.17–0.87). HR for obestatin was 0.38 (95% CI 0.11–1.24). Ghrelin is a potential prognostic factor for breast cancer death in male breast cancer. Patients with tumors expressing ghrelin have a 2.5-fold lower risk for breast cancer death than those lacking ghrelin expression. Drugs targeting ghrelin are currently being investigated in clinical studies treating metabolic or nutritional disorders. Ghrelin should be further evaluated in forthcoming studies as a prognostic marker with the aim to be included in decision algorithms.

Highlights

Male breast cancer (MBC) accounts for approximately 0.7% of all breast cancer cases in the Nordic countries[1], and 1% in the US2
Ghrelin gene-derived splice forms are overexpressed in breast cancer which could suggest that an imbalance in the regulation of the ghrelin system might lead to or influence breast tumor pathogenesis[33,37,38]
The results suggest that survival is better in MBC patients with tumors expressing ghrelin, than among patients whose tumors are non-IR

Summary

Introduction

Male breast cancer (MBC) accounts for approximately 0.7% of all breast cancer cases in the Nordic countries[1], and 1% in the US2. Significant differences regarding DNA aberrations compared to FBC has been demonstrated using comparative genome hybridization, and a new subgroup unique for male patients was identified[13]. These findings suggest that MBC may be a separate tumor entity from FBC. Its involvement in cell proliferation[21,22,23] together with the effect on GH levels by the ghrelin axis[14], gives ghrelin a potential role in tumorigenesis[24] Another interesting aspect is that low ghrelin levels are correlated to obesity, a known risk factor for breast cancer[25,26]. Knowledge about the prognostic impact of many routinely used clinicopathological parameters in MBC is limited and contradictory[39,40] and since MBC might not be exactly the same disease as FBC, it is important to investigate the role of new potential biomarkers as well as to evaluate how to best assess different biomarkers in MBC

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Methods

Conclusion