Publication Date

2015-02-18

Availability

Embargoed

Embargo Period

2017-02-17

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2014-12-14

First Committee Member

Marc Lippman

Second Committee Member

Diana Lopez

Third Committee Member

Stefan Gluck

Fourth Committee Member

Nanette Bishopric

Fifth Committee Member

Enrique Mesri

Abstract

The transformation from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells isolated from wild-type neu expressing mice and identified the E3 ligase HACE1 as a HER2 cooperative tumor suppressor gene. Loss of HACE1 expression is commonly seen in clinical multiple cancer datasets including breast cancer. HACE1 down-regulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Rac1 partially transforming these cells. Overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. While the knockdown of HACE1 or overexpression of HER2 alone in HMECs is not sufficient for tumorigenesis, HER2 overexpression combined with HACE1 down-regulation fully transforms HMECs resulting in robust tumor formation. The pharmaceutical interference of Rac function abrogates the effects of HACE1 loss both in vitro and in vivo resulting in dramatic reduction in tumor burden. Our work supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac targeted therapies.

Keywords

Breast Cancer; Tumor Suppressor; Rac

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