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

Abstract

Estrogen-receptor alpha (ER )-positive and progesterone receptor negative (ER+/PR-) breast ductal carcinomas comprise approximate15- 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 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. Moreover, we reported that the growth of ER+/PRmammary tumors arising in our mouse models depends not only on estrogen, but also on progesterone, despite the absence of detectable PR by immunohistochemistry, providing a rationale for targeting PR signaling for the inhibition of ER+/PR- breast cancer development. Here we report that loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling and ER through delaying EGFR degradation and sustaining EGFR signaling. In addition, we demonstrate that treatment of ER+/PR- mammary tumor cells with NVPBEZ235 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.

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Document Details

Document Type
Technical Report
Publication Date
Nov 01, 2011
Accession Number
ADA561140

Entities

People

  • Hua Xiao

Organizations

  • Michigan State University

Tags

DTIC Thesaurus Topics

  • Biomedical And Dental Materials
  • Breast Cancer
  • Cell Physiological Processes
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Confocal Microscopy
  • Genetics
  • Health Services
  • Intracellular Membranes
  • Proteins
  • Proteomics

Fields of Study

  • Biology

Readers

  • Breast cancer cell signaling and growth regulation.
  • Geochemistry
  • Molecular Biology and Genetics

Technology Areas

  • Biotechnology