Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Molecular pathways and therapeutic targets for triple-negative breast cancer (#140)

Mariska Miranda 1 2 , Fares Al-Ejeh 1 , Peter Simpson 3 , Georgia Trench 4 , Sunil Lakhani 3 5 , Kum Kum Khanna 1
  1. Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Qld, Australia
  2. UQ School of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. The University of Queensland, UQ Centre for Clinical Research (UQCCR), Brisbane, Qld, Australia
  4. Cancer Genetics, Queensland Institute of Medical Research, Brisbane, Qld, Australia
  5. Pathology Queensland, The Royal Brisbane & Women’s Hospital, Brisbane, Qld, Australia

Breast cancer is the leading cause of cancer-related mortality among women worldwide. Triple negative breast cancer is a subtype of breast cancer known for its aggressive behaviour and poor prognosis. Currently there has been a shift from using empirically derived agents that inhibit tumor cell growth and/or survival, to molecular therapies that target specific molecules that regulate these and other important biological processes. Despite the success of some new-targeted therapies to treat breast cancer, the outlook for the majority of patients with triple negative breast cancer (TNBC) remains poor. Therefore we have utilized the KinexTM antibody array to resolve potential new targetable “nodes”.  We screened 43 primary breast cancer biopsies (16 TNBC, 16 ER/PR positive and 11 HER2-positive) and 16 breast cancer cell lines for protein/phosphoprotein levels. Unsupervised hierarchical clustering of protein/phosphoprotein levels revealed two distinct subgroups of TNBC. Western blotting and Proteome ProfilerTM Arrays (R&D Systems) were used to validate deregulated proteins/phosphoproteins in TNBC. Pathway analysis revealed that one subgroup of TNBC exploits overlapping and cross-talking networks (FAK, MAPK/ERK, PLCg1/PDK1, p38aMAPK/JNK and S6 kinase signaling) for survival. These signaling networks are downstream from elevated activation of integrins, EGFR, and Insulin-like growth factor 1 receptor (IGF1R). We have then investigated the effect of inhibition of these pathways in a panel of breast cancer cell lines that represent different subtypes. Functional evaluation of defined pathway alterations in vitro and in vivo could lead to the development of more effective therapies for TNBC and improve morbidity by targeting new proteins/pathways that drive tumor progression and growth in TNBC patients.