A senescent-immune reserve niche hypothesis for incomplete lobular involution in the aging breast
Abstract
Breast cancer incidence rises with age and peaks across the menopausal transition, yet why some postmenopausal lobules persist, and why that persistence predicts cancer risk, remains unresolved. Incomplete age-related lobular involution is one of the strongest tissue-level predictors of subsequent breast cancer, but it is still commonly viewed as passive failure of hormonally driven regression. This Review proposes a different framework: persistent lobules are maintained by an active reserve niche that outlasts its reproductive function. Recent human tissue studies show that persistent postmenopausal lobules retain a proliferation-competent epithelial state and that immune cells accumulate at the lobular boundary without being positioned to engage p16INK4a-positive epithelial foci; in a separate longitudinal cohort, senescence-linked programs reverse their association with involution pace across menopause. We integrate these findings with breast epidemiology and mammary stromal biology, and draw on reserve systems in skeletal muscle, hematopoiesis, and postmenopausal endometrium as sources of candidate mechanisms and testable predictions rather than as evidence for the breast. We argue that menopause is a biological control point at which tissue fate diverges, and that what distinguishes persistence from resolution is not the amount of inflammation present but whether immune effectors are spatially positioned to execute clearance. This shifts attention from epithelial quantity to microenvironmental state and identifies the perimenopausal window as a promising interval for biomarker-guided risk stratification and prevention.
Related
- Lobular panniculitis without sicca symptoms: A rare male presentation of Sjögren's disease
- 1141 Spatial immune profiling across the lobular breast cancer continuum reveals progressive immune exclusion from precursor lesion to invasive disease
- Surprisal-based large language models reveal immunologic insights in lobular breast cancer
- High intestinal obstruction secondary to peritoneal metastases from invasive lobular breast carcinoma: A case report of an unusual presentation
- Integrated Transcriptomic Analysis Reveals Distinct Molecular and Immune Microenvironment Features of Peutz–Jeghers Syndrome-Associated Lobular Endocervical Glandular Hyperplasia and Gastric-Type Endocervical Adenocarcinoma
BibTeX
@misc{lue2026senescentimmune,
title = {{A senescent-immune reserve niche hypothesis for incomplete lobular involution in the aging breast}},
author = {Jaida C. Lue and Darren J. Baker and Amy C. Degnim and Stacey J. Winham and Mark E. Sherman and Derek C. Radisky},
howpublished = {arXiv},
year = {2026},
month = sep,
doi = {10.48550/arxiv.2605.13902},
eprint = {2605.13902},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2605.13902},
}
RIS
TY - UNPB
TI - A senescent-immune reserve niche hypothesis for incomplete lobular involution in the aging breast
AU - Jaida C. Lue
AU - Darren J. Baker
AU - Amy C. Degnim
AU - Stacey J. Winham
AU - Mark E. Sherman
AU - Derek C. Radisky
PY - 2026
DA - 2026/09/11
PB - arXiv
DO - 10.48550/arxiv.2605.13902
UR - https://arxiv.org/abs/2605.13902
AB - Breast cancer incidence rises with age and peaks across the menopausal transition, yet why some postmenopausal lobules persist, and why that persistence predicts cancer risk, remains unresolved. Incomplete age-related lobular involution is one of the strongest tissue-level predictors of subsequent breast cancer, but it is still commonly viewed as passive failure of hormonally driven regression. This Review proposes a different framework: persistent lobules are maintained by an active reserve niche that outlasts its reproductive function. Recent human tissue studies show that persistent postmenopausal lobules retain a proliferation-competent epithelial state and that immune cells accumulate at the lobular boundary without being positioned to engage p16INK4a-positive epithelial foci; in a separate longitudinal cohort, senescence-linked programs reverse their association with involution pace across menopause. We integrate these findings with breast epidemiology and mammary stromal biology, and draw on reserve systems in skeletal muscle, hematopoiesis, and postmenopausal endometrium as sources of candidate mechanisms and testable predictions rather than as evidence for the breast. We argue that menopause is a biological control point at which tissue fate diverges, and that what distinguishes persistence from resolution is not the amount of inflammation present but whether immune effectors are spatially positioned to execute clearance. This shifts attention from epithelial quantity to microenvironmental state and identifies the perimenopausal window as a promising interval for biomarker-guided risk stratification and prevention.
ER -