Proton-irradiated breast cells: molecular points of view.

Valentina Bravatà,Maria C Gilardi,Pietro Pisciotta,Gaetano Savoca,Giuseppe A P Cirrone,Giacomo Cuttone,Lorenzo Manti,Giusi I Forte,Francesco P Cammarata,Luigi Minafra,Concetta Scazzone,Giorgio Russo,Giada Petringa

doi:10.1093/jrr/rrz032

Abstract

Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome

Highlights

The idea that genes may function as biomarkers of disease response provides the rationale for the development of molecularly based signatures to predict response to radiation treatment in cancer, including breast cancer (BC)
Supplementary file 2 contains a second-order polynomial fitting analysis conducted for each immunological molecule, in order to study their trend according to time and dose delivered
In order to test the effects of the proton beam irradiation on cell loss of reproductive capacity, MCF10A non-tumorigenic mammary epithelial cells, and MCF7 and MDA-MB-231 tumorigenic BC cell lines were irradiated with the doses of 0.5, 2, 4, 6 and 9 Gy

Summary

Introduction

The idea that genes may function as biomarkers of disease response provides the rationale for the development of molecularly based signatures to predict response to radiation treatment in cancer, including breast cancer (BC). Microarray-based expression studies have demonstrated their relevance in the comprehension of cancer behavior as well as in cancer care. It is well known that BC is the most common cancer in women, highly heterogeneous at both the clinical and molecular level and showing distinct subtypes associated with different clinical outcomes; the need to develop targeted therapeutic strategies [1, 2]. Gene expression profile (GEP) studies allowed BC patients to be divided into clinically relevant subtypes because of their distinct gene expression patterns, associated with different prognoses.

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