Abstract
Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.
Highlights
Breast cancer (BC) is the most common cancer in women and ranks second worldwide, contributing to 11.6% of all new cases
The expression levels of the BCSC markers ALDH1, CD44+ and CD24−/low was evaluated in 2D and 3D cultures after Ionizing Radiation (IR), with variations in the expression found between the two culture models used
Our results showed that histone deacetylases (HDACs)-2 was significantly upregulated with increasing IR dose in the MDA-MB-231 positive subpopulation grown in 3D+lrECM culture, which could be related to the recapitulation of a stem cell niche
Summary
Breast cancer (BC) is the most common cancer in women and ranks second worldwide, contributing to 11.6% of all new cases. BC ranks fifth for mortality worldwide, contributing to 6.6% of the total cancer deaths [1]. BC is a complex disease with high inter- and intra-tumor heterogeneity [2]. Tumor subtype and resistance to treatment are involved in BC development and growth as well as cancer stem cells (CSCs), a small portion of cells found within tumors [3]. CSCs were first reported in 1996 based on identical chromosomal alterations in contiguous regions of the mammary epithelium [4,5,6]. The concept of CSCs has been around for decades and is still
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