Accession Number:

ADA535362

Title:

Unraveling the Molecular Mechanism(s) Underlying ER+/PR- Breast Tumorigenesis Using a Novel Genetically Engineered Mouse Model

Descriptive Note:

Annual rept. 1 Sep 2009-31 Aug 2010

Corporate Author:

MICHIGAN STATE UNIV EAST LANSING

Personal Author(s):

Report Date:

2010-09-01

Pagination or Media Count:

17.0

Abstract:

Estrogen-receptor alpha ERalpha-positive Progesterone receptor negative ERPR- breast ductal carcinomas comprise approximate 15-25 of human breast cancers. However, molecular mechanisms underlying the development of this subtype of breast cancer remain poorly understood. This project is to study the molecular mechanisms underlying ERPR- breast tumorigenesis. Specifically, we proposed to determine genetic and epigenetic alterations in the initiation and progression of ERPR- mammary tumors arising in Tip30--MMTV-neu mice. We previously demonstrated that Tip30 deletion in MMTV-Neu mice significantly accelerates the formation of ERPR- mammary tumors. An unbiased DNA microarray analysis revealed that Tip30 deletion resulted in increased activation of cAMP-mediated signaling, EGF signaling, IGF signaling and PI3KAKT signaling in ERPR- mammary tumors. Here we report that loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling and ERalpha. Moreover, Tip30 deletion led to delayed EGFR degradation and sustained EGFR signaling, and treatment of ERPR- mammary tumor cells with NVP-BEZ235 in combination with tamoxifen significantly inhibited cell proliferation compared to treatment with either NVP-BEZ235 or tamoxifen alone. Together, our data suggest NVP-BEZ235 in combination with tamoxifen as a potential therapeutic strategy for treating ERPR- breast cancers that are resistant to tamoxifen or trastuzumab.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE