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

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.

Attribution of Ghrelin to Cancer; Attempts to Unravel an Apparent Controversy

“…It also could be considered an adjuvant therapy like other novel therapies suggested (147, 148) to reduce toxicity of conventional therapies (149). In support, three cohorts reported positive prognostic significance of ghrelin immunostainings in breast cancer tissue (96, 97, 103). These cohorts consisted of men or women patients with hormone-dependent breast cancer and mean age of women cases was in post-menopausal range.…”

“…Likewise, ghrelin expression was associated with favorable breast cancer-specific survival in male breast cancer patients, irrespective of primary tumor size and lymph node involvement. Ghrelin status did not affect response to adjuvant endocrine therapy among ER-positive cases (97). Further, ghrelin positivity of tumor cells was associated with a decreased mortality when comparing 190 patients who died of breast cancer and 190 breast cancer patients as living controls (127).…”

“…Similarly, 81.2% of 197 male patients with breast cancer had ghrelin positive tumor cells. The intensity of ghrelin staining was not uniform in different parts within a tumor, suggesting a shift from production of native ghrelin to other variants of ghrelin in malignant conditions (97). Non-malignant breast tissue expressed no ghrelin (58), or lower levels of ghrelin compared to malignant tissue (11).…”

Immunohistochemical analysis of ghrelin expression in various types of adrenal tumors

“…miRNAs are small (30-32)-nucleotide noncoding RNA that act as regulators of posttranscriptional stability and/or translation of RNA (mRNA) [31]. Certain types of miRNAs are higher in ACC tissues than in ACA [31][32][33]. It is assumed that miRNAs might interfere with translation or enhance the degradation of ghrelin.…”

“…Ghrelin gene-derived splice variants are overexpressed in breast cancer, which suggests that an imbalance in the ghrelin system's regulation may be associated with the pathogenesis of breast tumor [33]. Perhaps, a similar mechanism is involved in the development of adrenal tumors.…”