Research Papers:

p16INK4a suppresses BRCA1-deficient mammary tumorigenesis

Alexandria Scott, Feng Bai, Ho Lam Chan, Shiqin Liu, Jinshan Ma, Joyce M Slingerland, David J. Robbins, Anthony J. Capobianco and Xin-Hai Pei _

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Oncotarget. 2016; 7:84496-84507. https://doi.org/10.18632/oncotarget.13015

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Alexandria Scott1,2, Feng Bai1, Ho Lam Chan1, Shiqin Liu1, Jinshan Ma1, Joyce M Slingerland3, David J. Robbins1,4, Anthony J. Capobianco1,4, Xin-Hai Pei1,2,4

1Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

2The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

3Braman Family Breast Cancer Institute, Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

4Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

Correspondence to:

Xin-Hai Pei, email: xhpei@med.miami.edu

Keywords: p16INK4a, senescence, brca1, breast cancer

Received: June 30, 2016     Accepted: October 25, 2016     Published: November 02, 2016


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.

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