p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress

Sep 21, 2026

Uploaded by Logic

Significant efforts focus on identifying targetable genetic drivers that support solid tumor growth and/or enhance metastatic capability. During tumor development, physiological and pharmacological pressures trigger adaptive strategies across cancer subpopulations, helping cells endure stressful microenvironments, though mechanisms remain unclear. This study shows the p66ShcA redox protein is essential for survival under physiological stressors in poor-outcome breast cancers, promoting glucose and glutamine metabolic reprogramming to support glutathione synthesis and redox balance.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Abstract

Introduction

Breast cancer heterogeneity and resistance

Stress adaptation and ROS biology

Redox balance and the need for mechanism-level insight

Redox Biology 70 (2024) 103028 Contents lists available at ScienceDirect Redox Biology journal [homepage:](homepage: www.elsevier.com/locate/redox)[ www.elsevier.com/locate/redox](homepage: www.elsevier.com/locate/redox) | p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress
Kyle Lewis a, b, 1, Rachel La Selva a, c, 1, Elias Maldonado a, c, Matthew G. Annis d, Ouafa Najybb, d, Eduardo Cepeda Ca˜nedo a, c, Stephanie Totten a, c, Steven H´ebert a, Val´erie Sabourina, Caitlynn Mirabellia, c, Emma Ciccolinia, c, Camille Lehu´ed´e d, Luc Choini`ered, Mariana Russo d, Daina Avizonisd, Morag Park b, c, d, g, Julie St-Pierre e, Claudia L. Kleinmana, f, Peter
M. Siegel b, c, d, g, Josie Ursini-Siegel a, b, c, g, *
a Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada
b Department of Biochemistry, McGill University, Montreal, QC, Canada c Division of Experimental Medicine, McGill University, Montreal, QC, Canada d Goodman Cancer Institute, McGill University, Montreal, QC, Canada
e Department of Biochemistry, Microbiology and Immunology and Ottawa Institute of Systems Biology, University of Ottawa, ON, Canada f Department of Human Genetics, McGill University, Montreal, QC, Canada
g Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada | | | | --- | --- | --- | | A R T I C L E I N F O | | A B S T R A C T | | Keywords:
p66ShcA
Breast cancer Oxidative stress Metabolic plasticity Glutathione Anoikis | | Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumorsand/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell subpopulations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress. | 1. Introduction Breast cancer is a heterogeneous disease that is classified into luminal A/B, HER2 and basal/triple negative subtypes [1]. Although targeted therapies have significantly improved survival outcomes for women diagnosed with early-stage estrogen receptor (ER)+ and HER2+ breast cancer, subsets of patients diagnosed with advanced disease develop resistance [2,3]. In addition, many triple negative breast cancer (TNBC) patients develop chemoresistance [4]. These differences in patient outcome arise from tumor plasticity, which is influenced by intrinsic and microenvironmental changes that impact gene expression and metabolic networks, allowing breast cancers to adapt to and exploit physiologic stressors [5]. Invariably, stress-educated cancers acquire metastatic properties, leading to worse survival outcomes. However, the m

FAQs

What does p66ShcA enable in poor-outcome breast cancers under stress?

p66ShcA is essential for survival in response to physiological stressors such as anchorage independence and nutrient deprivation.

How does p66ShcA support adaptive redox management?

It promotes glucose and glutamine metabolic reprogramming, increasing capacity for catabolic metabolism and glutathione synthesis to maintain ATP and redox balance.

Why is physiological/chronic ROS linked to more aggressive cancer behavior?

Moderate ROS elevation can enhance aggressive properties through mechanisms affecting tumor suppressors, genomic stability, stem-like phenotypes, and inflammation, contributing to metastatic fitness.

Sep 21, 2026

Uploaded by Logic