Expression of beclin-1 in the microenvironment of invasive ductal carcinoma of the breast: correlation with prognosis and the cancer-stromal interaction.

Akemi Morikawa,Manabu Futamura,Tamotsu Takeuchi,Chiemi Saigo,Yusuke Kito,Takuji Sakuratani,Kazuhiro Yoshida,Rajeev Samant

doi:10.1371/journal.pone.0125762

Abstract

We examined the pathobiological properties of beclin-1, which is a key regulator of autophagosome formation in invasive ductal carcinoma of the breast, with a particular focus on the cancer microenvironment. Immunohistochemistry demonstrated that cancer cells and stromal mesenchymal cells expressed beclin-1 in 68 and 38 of 115 invasive ductal cancers, respectively. Expression of beclin-1 in cancer or stromal cells alone did not correlate with patient prognosis. In contrast, loss of beclin-1 in cancer cells and overexpression in stromal mesenchymal cells was associated with local cancer recurrence, postoperative lymph node metastasis, and a poor disease-free survival rate. A comprehensive gene expression analysis was performed on a co-culture of breast cancer cells and mesenchymal stromal cells, that latter of which either expressed beclin-1 or was depleted of beclin-1 by siRNA. Notably, siRNA-mediated downregulation of beclin-1 in mesenchymal cells co-cultured with breast cancer cells decreased the levels of various pro-inflammatory cytokines, their receptors, and collagen receptors. Quantitative reverse transcription polymerase chain reaction analysis confirmed that reduction of stromal beclin-1 expression decreased the expression of IL-1β and collagen receptor discoidin domain receptor 2 (DDR2). Microenvironmental IL-1β is believed to play an important role in tumor invasion. Recent work has also indicated that overexpression of DDR2 contributes to breast cancer invasion and lymph node metastasis. Taken together, these findings indicate beclin-1 expression in the stroma might be important for shaping the breast cancer microenvironment and thus could be a potent molecular target in patients with invasive ductal carcinoma of the breast.

Highlights

Autophagy is the process of self-digestion in which lysosomal degradation is used to maintain cellular viability during periods of metabolic stress such as starvation [1,2]
We examined beclin-1 expression in archived pathological tissue specimens from patients with invasive ductal carcinoma
Dong et al determined that low expression of beclin-1 was associated with a worse 5-year overall survival rate in ER-positive and HER2-negative breast cancer [22]

Summary

Introduction

Autophagy is the process of self-digestion in which lysosomal degradation is used to maintain cellular viability during periods of metabolic stress such as starvation [1,2]. Autophagy is important for tumor cell survival under starvation conditions. Autophagy defects are associated with increasing carcinogenesis [3,4]. Beclin-1 is important at the major step in autophagic pathways, from autophagosome formation to autophagosome/endosome maturation [5,6]. Beclin is a key protein and reliable biomarker of autophagy in various cancers. Exogenous expression of beclin-1 in MCF-7 breast cancer cells promoted autophagy, inhibited cell growth, and decreased tumorigenesis in nude mice [5]. Beclin-1-dependent autophagy is required for the tumorigenicity of breast cancer stem-like/progenitor cells [8]. Beclin-1 expression may have a dual role in breast carcinogenesis, acting both to promote and to suppress tumor progression

Methods

Results

Conclusion