Abstract

Simple SummaryDuring the past decades the achievements made in treating cancers have significantly improved the survival of patients. However, cancer is still one of the leading causes of mortality. It is suggested that treatment failure is mediated by a subpopulation of tumor cells named cancer stem cells that can survive after treatment and promote cancer relapse. Targeting these cells is important to improve cancer therapy. The aim of our study is to determine the effect of a human ribonuclease variant on breast cancer cells grown in 3D and on cancer stem cells. Moreover, we study its effect on the ability of breast cancer cells to migrate and produce metastasis, responsible for about 90% of cancer deaths. We show that this ribonuclease arrests tumor cells grown in 3D without affecting normal breast cells, and this significantly inhibits cancer stem cell development. Additionally, it reduces the migratory and invasive capacities of tumor cells.Despite the significant advances in cancer research made in recent years, this disease remains one of the leading causes of death worldwide. In part, this is due to the fact that after therapy, a subpopulation of self-renewing tumor cells can survive and promote cancer relapse, resistance to therapies and metastasis. Targeting these cancer stem cells (CSCs) is therefore essential to improve the clinical outcome of cancer patients. In this sense, multi-targeted drugs may be promising agents targeting CSC-associated multifocal effects. We have previously constructed different human pancreatic ribonuclease (RNase) variants that are cytotoxic for tumor cells due to a non-classical nuclear localization signal introduced in their sequence. These cytotoxic RNases affect the expression of multiple genes involved in deregulated metabolic and signaling pathways in cancer cells and are highly cytotoxic for multidrug-resistant tumor cell lines. Here, we show that these cytotoxic nuclear-directed RNases are highly selective for tumor cell lines grown in 3D, inhibit CSCs’ development and diminish the self-renewal capacity of the CSCs population. Moreover, these human RNase variants reduce the migration and invasiveness of highly invasive breast cancer cells and downregulate N-cadherin expression.

Highlights

  • Breast cancer (BC) is the second leading cause of cancer-related deaths among women worldwide [1]

  • We investigated the effect of NLSPE5 on a panel of three BC cell lines, representative of different subtypes of BC, and on two non-tumor breast cell lines, cultured in

  • NLSPE5 is highly cytotoxic against MDA-MB-231 and MCF7 cell lines but much less cytotoxic for BT474 cell line (Table 1)

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Summary

Introduction

Breast cancer (BC) is the second leading cause of cancer-related deaths among women worldwide [1]. The therapeutic options of the affected women are decided by evaluating a number of biomarkers: the presence of estrogen and progesterone receptors (ER and PR), an excess level of human epidermal growth factor receptor 2 (HER2) protein, and/or extra copies of the HER2 gene [2] Using these biomarkers, BC is classified into three major molecular subtypes: hormone sensitive (ER+/PR+ or ER+/PR−, HER2−); HER2 amplified (ER−/PR− or ER+/PR−, HER2+); and triple negative (TNBC) (ER−/PR−/HER2−) [3]. It has been shown that TNBC is enriched in cancer stem cells (CSCs) [4], which possess unlimited capacity for self-renewing and inherent resistance to chemotherapy. These capacities allow the post-treatment remnant cells to give rise to a differentiated cancer cell progeny, produce tumor recurrence and metastases [5,6]

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