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Updated: Mar 12, 2026
Modeling Breast Cancer via an Intraductal Injection of Cre-expressing Adenovirus into the Mouse Mammary Gland
Published on: June 7, 2019
p16INK4a suppresses BRCA1-deficient mammary tumorigenesis
Alexandria Scott1,2, Feng Bai1, Ho Lam Chan1
1Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Abstract:
Senescence prevents the proliferation of genomically damaged, but otherwise replication competent cells at risk of neoplastic transformation. p16INK4A (p16), an inhibitor of CDK4 and CDK6, plays a critical role in controlling cellular senescence in multiple organs. Functional inactivation of p16 by gene mutation and promoter methylation is frequently detected in human breast cancers. However, deleting p16 in mice or targeting DNA methylation within the murine p16 promoter does not result in mammary tumorigenesis. How loss of p16 contributes to mammary tumorigenesis in vivo is not fully understood.In this article, we reported that disruption of Brca1 in the mammary epithelium resulted in premature senescence that was rescued by p16 loss. We found that p16 loss transformed Brca1-deficient mammary epithelial cells and induced mammary tumors, though p16 loss alone was not sufficient to induce mammary tumorigenesis. We demonstrated that loss of both p16 and Brca1 led to metastatic, basal-like, mammary tumors with the induction of EMT and an enrichment of tumor initiating cells. We discovered that promoter methylation silenced p16 expression in most of the tumors developed in mice heterozygous for p16 and lacking Brca1. These data not only identified the function of p16 in suppressing BRCA1-deficient mammary tumorigenesis, but also revealed a collaborative effect of genetic mutation of p16 and epigenetic silencing of its transcription in promoting tumorigenesis. To the best of our knowledge, this is the first genetic evidence directly showing that p16 which is frequently deleted and inactivated in human breast cancers, collaborates with Brca1 controlling mammary tumorigenesis.
Insights
Loss of p16INK4A (p16) rescues senescence in Brca1-deficient cells, promoting mammary tumors. Combined p16 and Brca1 loss drives metastatic breast cancer, highlighting p16
Area of Science:
- Oncology
- Cellular Biology
- Cancer Genetics
Background:
- Cellular senescence, regulated by p16INK4A (p16), prevents cancer by halting damaged cell proliferation.
- p16 inactivation via mutation or methylation is common in human breast cancers, but its role in mammary tumorigenesis is unclear.
- Brca1 deficiency in mice causes premature senescence, suggesting a link between Brca1, p16, and mammary tumor development.
Purpose of the Study:
- To investigate the role of p16INK4A (p16) in suppressing mammary tumorigenesis in Brca1-deficient settings.
- To elucidate the collaborative mechanisms between p16 loss and Brca1 deficiency in driving breast cancer progression.
Main Methods:
- Genetic manipulation in mouse models: disruption of Brca1 and modulation of p16.
- Analysis of mammary epithelial cell senescence and transformation.
- Characterization of tumor phenotypes, including metastasis, gene expression (EMT), and stem cell populations.
- Investigation of p16 promoter methylation in tumor development.
Main Results:
- Brca1 deficiency-induced senescence was rescued by p16 loss, enabling mammary epithelial cell transformation and tumor formation.
- Loss of both p16 and Brca1 resulted in aggressive, basal-like, metastatic mammary tumors with induced epithelial-mesenchymal transition (EMT) and enriched tumor-initiating cells.
- Epigenetic silencing of p16 via promoter methylation was observed in tumors from mice heterozygous for p16 and lacking Brca1.
Conclusions:
- p16INK4A (p16) functions as a critical suppressor of Brca1-deficient mammary tumorigenesis.
- Combined genetic loss of p16 and Brca1, along with epigenetic silencing of p16, synergistically promotes aggressive, metastatic breast cancer.
- This study provides the first genetic evidence for p16's collaborative role with Brca1 in controlling mammary tumor development.
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