Unraveling the Molecular Mechanism(s) Underlying ER+/PR- Breast Tumorigenesis Using a Novel Genetically Engineered Mouse Model
Abstract
Estrogen-receptor alpha (ERalpha)-positive Progesterone receptor negative (ER+/PR-) 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 mechanism(s) underlying ER+/PR- breast tumorigenesis. Specifically, we proposed to determine genetic and epigenetic alterations in the initiation and progression of ER+/PR- mammary tumors arising in Tip30-/-/MMTV-neu mice. We previously demonstrated that Tip30 deletion in MMTV-Neu mice significantly accelerates the formation of ER+/PR- mammary tumors. An unbiased DNA microarray analysis revealed that Tip30 deletion resulted in increased activation of cAMP-mediated signaling, EGF signaling, IGF signaling and PI3K/AKT signaling in ER+/PR- 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 ER+/PR- 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 ER+/PR- breast cancers that are resistant to tamoxifen or trastuzumab.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2010
- Accession Number
- ADA535362
Entities
People
- Hua Xiao
Organizations
- Michigan State University