p16INK4a suppresses BRCA1-deficient mammary tumorigenesis.
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.
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.|The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Alexandria
A
Scott
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Feng
F
Bai
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Ho Lam
HL
Chan
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Shiqin
S
Liu
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Jinshan
J
Ma
Braman Family Breast Cancer Institute, Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Joyce M
JM
Slingerland
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.|Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
David J
DJ
Robbins
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.|Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Anthony J
AJ
Capobianco
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.|The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.|Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Xin-Hai
XH
Pei
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics
D019313:BRCA1 Protein; D019941:Cyclin-Dependent Kinase Inhibitor p16
brca1; breast cancer; p16INK4a; senescence