Biological Aggressiveness of Subclinical No-Mass Ductal Carcinoma In Situ (DCIS) Can Be Reflected by the Expression Profiles of Epithelial-Mesenchymal Transition Triggers.

Bartlomiej Szynglarewicz,Rafal Matkowski,Agnieszka Halon,Przemyslaw Biecek,Piotr Kasprzak,Piotr Donizy

doi:10.3390/ijms19123941

Abstract

Epithelial-mesenchymal transitions (EMTs) have been recently implicated in the process of cancer progression. The aim of this study was to assess how the preoperative expression patterns of EMT biomarkers correlate with the risk of postoperative invasion in ductal carcinoma in situ (DCIS) found on stereotactic breast biopsies. N-cadherin, Snail1, and secreted protein acidic and rich in cysteine (SPARC) immunoreactivity was observed in 8%, 62%, and 38% of tumors, respectively. Snail1 and SPARC expressions were significantly related to N-cadherin expression and to each other. The postoperative upgrading rate was associated with a positive preoperative expression of all biomarkers. Significance of Snail1 and SPARC persisted in multivariate analysis, but the impact of SPARC on invasion was more significant. When these two EMT triggers were considered together, the risk of invasion did not significantly differ between the subtypes of DCIS with single positive expression (SPARC−/Snail1+ vs. SPARC+/Snail1−). However, it was significantly lower in single-positive DCIS when compared to lesions of a double-positive profile (SPARC+/Snail1+). Moreover, there were no cases in the double-negative DCIS (SPARC−/Snail1−), with foci of infiltrating cancer found postoperatively in residual postbiopsy lesions. In contrast, DCIS with a combined high SPARC and Snail1 expression (intermediate or strong) had an invasive component in 66–100% of tumors.

Highlights

Since the implementation of mammographic screening programs, the incidence of early breast cancer, in situ lesions, and borderline proliferations has increased dramatically [1]
Molecular changes during Epithelial-mesenchymal transitions (EMTs) are regulated by several transcription factors called EMT-inducers (Snail1, Snail2, ZEB1, ZEB2, TWIST, FOXC2, E47, TCF4), regulators of the extracellular matrix that facilitate the degradation of the basal membrane and surrounding tissues (SPARC, TGF-β, EGF, FGF), as well as molecules from related pathways (e.g., MAPK, P13K, Wnt, NF-κB, Notch, Hedgehog) [9]
We reported a significant association between the presence of final invasion following surgery in ductal carcinoma in situ (DCIS), diagnosed with a stereotactic vacuum-assisted biopsy as a pure in situ lesion, and a preoperative expression of molecules that trigger the early steps of EMT: Transcription factor Snail1, a direct E-cadherin repressor, and the multifunctional de-adhesive protein secreted protein acidic and rich in cysteine (SPARC), a key modulator of the tumor microenvironment

Summary

Introduction

Since the implementation of mammographic screening programs, the incidence of early breast cancer, in situ lesions, and borderline proliferations has increased dramatically [1]. Ductal carcinoma in situ (DCIS), which is usually diagnosed during a stereotactic biopsy of suspicious microcalcifications detected on a mammography, accounts for approximately 20% of all breast cancers [2,3]. Epithelial-mesenchymal transition (EMT) is a dynamic process whereby an immotile epithelial cell temporarily changes its morphology to a spindle-like shape and acquires the migratory and invasive properties of a mesenchymal cell. This allows for invasion through the basal membrane as well as the extracellular matrix and, migration to distant sites, where it reverts back into the epithelial phenotype [7]. Loss of E-cadherin expression and the concomitant upregulation or de novo expression of N-cadherin, referred to as a cadherin switch, is considered a hallmark of EMT [10]

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