SQSTM1/p62 and Mitochondrial Stress in Triple-Negative Breast Cancer: A Critical Pathology Perspective
6 affiliations
- 1Anatomic Pathology Unit, Department of Human Pathology of Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
- 2Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy
- 3Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
- 4Department for the Promotion of Human Science and Quality of Life, San Raffaele Roma University, 00166 Rome, Italy
- 5Clinical Pathology Unit, Department of Human Pathology of Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy
- 6Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
Abstract
Sequestosome 1 (SQSTM1/p62) links autophagy to cellular stress responses and can be assessed by immunohistochemistry. In triple-negative breast cancer (TNBC), however, its staining has no single biological interpretation. This selective narrative review examines human tissue studies alongside experimental evidence, focusing on the pathological assessment of mitochondrial stress. Human evidence remains limited—retrospective cohorts report inconsistent prognostic associations, and treatment-related changes are poorly characterized. Increased p62 can reflect enhanced synthesis or impaired degradation; mitochondrial clearance can also proceed without it. These observations explain why p62 staining alone cannot measure mitophagic flux. We propose assessing p62 distribution and abundance alongside mitochondrial content, oxidative damage and autophagy–lysosomal markers to describe exploratory tissue profiles. Each profile is linked to a proposed mechanism and to findings that would support or challenge that explanation. We consider baseline response associations separately from changes in residual disease, because complete responders lack residual invasive tumor for paired analysis. Mitochondrial turnover, respiratory function and genetic perturbation with rescue offer complementary ways to test the proposed dependencies. This framework provides a basis for investigating the relationship between mitochondrial damage, clearance, recovery and treatment persistence; its clinical relevance remains to be established.
Related
- Restoring mitochondrial redox balance enhances ribosome-associated quality control to mitigate Alzheimer’s disease pathology
- Primary Bone Vascular Neoplasms: An Integrated Biological Perspective from Bone Pathology to Precision Oncology
- Perspective: When the most popular outcome measure becomes a problem: a critical perspective on PROMs in orthopedics.
- Operationalising digital and AI pathology in translational research and drug development: an infrastructure and regulatory perspective from biobank to companion diagnostic.
- Mitochondrial folate transport becomes essential in serine/glycine-starved triple-negative breast cancer
BibTeX
@article{zuccala2026sqstm1p62,
title = {{SQSTM1/p62 and Mitochondrial Stress in Triple-Negative Breast Cancer: A Critical Pathology Perspective}},
author = {Valeria Zuccalà and Teresa Maria Martorana and Ludovica Pepe and Ida Rizzuto and Giuliana Ciappina and Carmelo Sofia and Maria Adele Marino and Mariamena Arbitrio and Riccardo Cavaliere and Massimiliano Berretta and Giovanni Tuccari and Vincenzo Fiorentino and Antonio Ieni},
journal = {Cancers},
year = {2026},
month = nov,
doi = {10.3390/cancers18213589},
url = {https://www.mdpi.com/2072-6694/18/21/3589},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SQSTM1/p62 and Mitochondrial Stress in Triple-Negative Breast Cancer: A Critical Pathology Perspective
AU - Valeria Zuccalà
AU - Teresa Maria Martorana
AU - Ludovica Pepe
AU - Ida Rizzuto
AU - Giuliana Ciappina
AU - Carmelo Sofia
AU - Maria Adele Marino
AU - Mariamena Arbitrio
AU - Riccardo Cavaliere
AU - Massimiliano Berretta
AU - Giovanni Tuccari
AU - Vincenzo Fiorentino
AU - Antonio Ieni
PY - 2026
DA - 2026/11/09
JO - Cancers
DO - 10.3390/cancers18213589
UR - https://www.mdpi.com/2072-6694/18/21/3589
AB - Sequestosome 1 (SQSTM1/p62) links autophagy to cellular stress responses and can be assessed by immunohistochemistry. In triple-negative breast cancer (TNBC), however, its staining has no single biological interpretation. This selective narrative review examines human tissue studies alongside experimental evidence, focusing on the pathological assessment of mitochondrial stress. Human evidence remains limited—retrospective cohorts report inconsistent prognostic associations, and treatment-related changes are poorly characterized. Increased p62 can reflect enhanced synthesis or impaired degradation; mitochondrial clearance can also proceed without it. These observations explain why p62 staining alone cannot measure mitophagic flux. We propose assessing p62 distribution and abundance alongside mitochondrial content, oxidative damage and autophagy–lysosomal markers to describe exploratory tissue profiles. Each profile is linked to a proposed mechanism and to findings that would support or challenge that explanation. We consider baseline response associations separately from changes in residual disease, because complete responders lack residual invasive tumor for paired analysis. Mitochondrial turnover, respiratory function and genetic perturbation with rescue offer complementary ways to test the proposed dependencies. This framework provides a basis for investigating the relationship between mitochondrial damage, clearance, recovery and treatment persistence; its clinical relevance remains to be established.
SN - 2072-6694
ER -