Targeting the UPR to Circumvent Endocrine Resistance in Breast Cancer

Abstract

An endocrine therapy is the most effective means to (initially) manage many hormone-dependent breast cancers. Unfortunately, almost 50% of estrogen receptor positive (ER+) breast cancers fail to respond (de novo resistant) and many others recur following an apparently initial response. We have now shown that cells respond to the stress of these therapies by activating the unfolded protein response (UPR). A central component of the UPR, and that which confers its prosurvival activities, is driven by the unconventional (cytosolic) splicing of XBP1 by the endoribonuclease function of IRE1. We screened small molecule libraries against IRE1 in silico and tested the top predicted hits for their abilities to inhibit XBP1s production and breast cancer cell proliferation, and to potentially reverse resistance to AEs. The most effective compound (N-(4-Phenoxy-phenyl)-2-(5-pyridin-3-yl-2H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; NPPTA) was selected for further study and is the initial focus of this IDEA Expansion application.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 2014
Accession Number
ADA613724

Entities

People

  • Ayesha N. Shajahan
  • Jacqueline Smith
  • Milton Brown
  • Robert Clarke

Organizations

  • Georgetown University

Tags

DTIC Thesaurus Topics

  • Alcohols
  • Apoptosis
  • Autophagy
  • Breast Cancer
  • Cell Physiological Processes
  • Cells
  • Estrogens
  • Indicator Dyes
  • Inhibition
  • Inhibitors
  • Molecules
  • Neoplasms
  • Polymerase Chain Reaction
  • Proteins
  • Resistance
  • Small Molecules
  • Surface Plasmon Resonance

Readers

  • Breast cancer cell signaling and growth regulation.
  • Oncology