BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer

Maria Rita Dionísio,Alison Barroso,José Pimentel,Inês Conde,Joana Paredes,Márcia M C Marques,Marta T Pinto,Pedro Pereira,Fernando Schmitt,Daniel Preto,Madalena Gomes,André F Vieira,Vinícius Duval Da Silva,Jorge F Cameselle-Teijeiro,Ana Sofia Ribeiro,Mónica Oliveira,Rita Carvalho,Cristiano Souza

doi:10.3390/cells9112442

Abstract

Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44+CD24−/low. Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3–5 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients.

Highlights

Breast cancer is the second leading cause of brain metastases after lung cancer [1]
According to the cancer stem cell theory, cancer cells are considered to exist in different populations, some of which may have stem cells’ properties, such as self-renewal capacity, that may aid their adaptation to distant organs with distinct microenvironments
In order to understand the role of CSCs in breast cancer brain metastases, we took advantage of the MDA-MB-231 breast cancer metastatic cell model in order to evaluate if there was an enrichment of stem-like properties in breast cancer cells with organotropism to the brain

Summary

Introduction

Breast cancer is the second leading cause of brain metastases after lung cancer [1]. Of patients with metastatic breast cancer, 15–30% will develop brain metastases during the course of the disease [2].human epidermal growth factor receptor 2 (HER2)-overexpressing and triple-negative breast cancer (TNBC) patients are at higher risk of developing brain metastases [1,3,4,5].Metastatic breast cancer dissemination to the central nervous system (CNS) is accompanied by neurological impairments affecting both cognitive and sensory functions, as well as an extremely poor prognosis [6]. Breast cancer is the second leading cause of brain metastases after lung cancer [1]. Of patients with metastatic breast cancer, 15–30% will develop brain metastases during the course of the disease [2]. Human epidermal growth factor receptor 2 (HER2)-overexpressing and triple-negative breast cancer (TNBC) patients are at higher risk of developing brain metastases [1,3,4,5]. Metastatic breast cancer dissemination to the central nervous system (CNS) is accompanied by neurological impairments affecting both cognitive and sensory functions, as well as an extremely poor prognosis [6]. Strategies to treat brain metastases are still very limited. Therapies based in trastuzumab-containing regimens, bevacizumab, or small molecules inhibitors may be contemplated, as they significantly extend overall patient survival (OS) [9]

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