Publication Date

2017-08-08

Availability

Open access

Embargo Period

2017-08-08

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2017-03-01

First Committee Member

Xin-Hai Pei

Second Committee Member

Enrique Mesri

Third Committee Member

Wassif Khan

Fourth Committee Member

Xiang-Xi Mike Xu

Fifth Committee Member

Merce Jorda

Abstract

A major risk factor of breast cancer is aging. Aging is caused partly by cellular senescence, a tumor suppressive mechanism that prevents the proliferation of cells at risk of transformation. p16INK4A (p16), an inhibitor of CDK4 and CDK6, plays a critical role in controlling senescence. Functional inactivation of p16 is frequently detected in human breast cancers. However, loss of p16 alone in mice does not result in mammary tumorigenesis. How p16 loss contributes to mammary cell aging and tumorigenesis in vivo is not fully understood. We reported that senescence was induced in mammary epithelial cells (MECs) during aging with increased expression of p16. Loss of p16 abrogated senescence in MECs and increased mammary stem cell function. We showed that loss of Brca1, a tumor suppressor, in the mammary epithelium induced senescence with the induction of p16 and a decline of stem cell function, which was rescued by p16 loss. These data identify the role of p16 in suppressing Brca1-deficient function of mammary stem cells. Furthermore, we found that p16 loss transformed Brca1-deficient MECs and induced mammary tumors, though loss of p16 alone did not. We discovered that promoter methylation silenced p16 expression in most of the tumors developed in mice heterozygous for p16 and lacking Brca1. 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.

Keywords

breast cancer; stem cells; p16; Brca1; senescence; aging

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