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Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas

Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent...

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Autores principales: Martin-Castillo, Begoña, Lopez-Bonet, Eugeni, Cuyàs, Elisabet, Viñas, Gemma, Pernas, Sonia, Dorca, Joan, Menendez, Javier A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741696/
https://www.ncbi.nlm.nih.gov/pubmed/26474458
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author Martin-Castillo, Begoña
Lopez-Bonet, Eugeni
Cuyàs, Elisabet
Viñas, Gemma
Pernas, Sonia
Dorca, Joan
Menendez, Javier A.
author_facet Martin-Castillo, Begoña
Lopez-Bonet, Eugeni
Cuyàs, Elisabet
Viñas, Gemma
Pernas, Sonia
Dorca, Joan
Menendez, Javier A.
author_sort Martin-Castillo, Begoña
collection PubMed
description Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44(+)CD24(−/low) CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44(+)CD24(−/low) CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44(+)CD24(−/low) CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44(+)CD24(−/low) mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of “Trojan horse” approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes might inform on their CSC-determined sensitivity to trastuzumab, thus providing a better delineation of the predictive value of cHER2+ in BC by incorporating CSCs-driven intra-tumor heterogeneity into clinical decisions.
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spelling pubmed-47416962016-03-11 Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas Martin-Castillo, Begoña Lopez-Bonet, Eugeni Cuyàs, Elisabet Viñas, Gemma Pernas, Sonia Dorca, Joan Menendez, Javier A. Oncotarget Research Perspective Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44(+)CD24(−/low) CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44(+)CD24(−/low) CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44(+)CD24(−/low) CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44(+)CD24(−/low) mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of “Trojan horse” approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes might inform on their CSC-determined sensitivity to trastuzumab, thus providing a better delineation of the predictive value of cHER2+ in BC by incorporating CSCs-driven intra-tumor heterogeneity into clinical decisions. Impact Journals LLC 2015-10-12 /pmc/articles/PMC4741696/ /pubmed/26474458 Text en Copyright: © 2015 Martin-Castillo et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Perspective
Martin-Castillo, Begoña
Lopez-Bonet, Eugeni
Cuyàs, Elisabet
Viñas, Gemma
Pernas, Sonia
Dorca, Joan
Menendez, Javier A.
Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas
title Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas
title_full Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas
title_fullStr Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas
title_full_unstemmed Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas
title_short Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas
title_sort cancer stem cell-driven efficacy of trastuzumab (herceptin): towards a reclassification of clinically her2-positive breast carcinomas
topic Research Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741696/
https://www.ncbi.nlm.nih.gov/pubmed/26474458
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