Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Mariela A Moreno Ayala,Matías Luis Pidre,Antonela Sofia Asad,Aldo Creton,Adriana Seilicovich,Marianela Candolfi,Víctor Romanowski,Mercedes Imsen,Marina Isla Larrain,Alejandro Javier Nicola Candia,Camila Florencia Zuccato,María Florencia Gottardo

doi:10.1038/s41598-020-65381-7

Abstract

Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of HN analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (TNBC). The meta-analysis of transcriptomic data from The Cancer Genome Atlas indicated that HN and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of HN in TNBC biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous HN protected TNBC cells from apoptotic stimuli whereas shRNA-mediated HN silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer.

Highlights

Breast cancer is the most common cause of death by cancer in women[1]
Two membrane receptors have been identified that bind circulating HN: (i) a trimeric receptor composed by the ciliary neurotrophic factor receptor (CNTFR), the IL27R (WSX-1) and the 130 kDa glycoprotein, which can trigger the activation of RAS/MAPKs, PI3K, JNK and STAT3; (ii) the formyl peptide receptor-like 1 (FPRL-1 or FPR2), which induces signal-regulated extracellular kinase activation (ERK 1/2)[10]
Since the expression of HN has not been evaluated in breast cancer cells before, we first assessed the presence of HN and its mRNA in human and murine breast tumor cell lines

Summary

Introduction

Breast cancer is the most common cause of death by cancer in women[1]. new strategies have been developed for the treatment of breast tumors that express hormone receptors and/or human epidermal growth factor receptor 2 (Her2), there are no therapeutic options for patients with triple negative breast cancer (TNBC), for whom chemotherapy/radiotherapy remains the first-line treatment[2,3]. Two membrane receptors have been identified that bind circulating HN: (i) a trimeric receptor composed by the ciliary neurotrophic factor receptor (CNTFR), the IL27R (WSX-1) and the 130 kDa glycoprotein (gp130), which can trigger the activation of RAS/MAPKs, PI3K, JNK and STAT3; (ii) the formyl peptide receptor-like 1 (FPRL-1 or FPR2), which induces signal-regulated extracellular kinase activation (ERK 1/2)[10]. Activation of these receptors exerts cytoprotection in preclinical models of stroke, diabetes, Alzheimer’s disease, among other diseases[14]. Since HN overexpression was detected in gastric cancer[23], bladder tumor cells[24], and pituitary tumor cells[13,18], it was suggested that HN upregulation could play a role in tumorigenesis

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