Molecular Profiling of Grade III Invasive Ductal Breast Cancers Identifies PPM1D Amplification as a Therapeutic Target in Luminal and HER2 Tumours
R Natrajan, SM Rodriguez-Pinilla, MBK Lambros, DSP Tan, C Marchio, R Vatcheva, S Rayter, G Moreno-Bueno, LG Fulford, A Mackay, A Grigoriadis, K Fenwick, N Tamber, D Hardisson, A Tutt, J Palacios, H Buerger, CJ Lord, A Ashworth, JS Reis-Filho. ICR, London, United Kingdom; CNIO, Madrid, Spain; Instituto de Investigaciones Biomedicas Alberto Sols, Madrid, Spain; The Ludwig Institute for Cancer Research, London, United Kingdom; Hospital Universitario La Paz, Madrid, Spain; Hospital Virgen del Roco, Seville, Spain; Institute of Pathology, Paderborn, Germany
Background: Grade III (GIII) breast cancer encompasses a heterogeneous group of cancers with aggressive clinical behaviour. Our aims were to characterise the molecular genetic profiles of GIII invasive ductal carcinomas of no special type (IDC-NSTs) using high resolution microarray-based comparative genomic hybridisation (aCGH), and to identify recurrent amplicons harbouring putative therapeutic targets associated with luminal, HER2 and basal-like phenotypes.
Design: 95 grade III-IDC-NSTs were classified into luminal, HER2 and basal-like subgroups using a previously validated immunohistochemical panel. Tumour samples were microdissected and subjected to aCGH using a tiling path 32K bacterial artificial chromosome array platform. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was performed using previously validated short hairpin RNA (shRNA) constructs and a specific small molecule inhibitor.
Results: We demonstrate that basal-like and HER2 tumours are characterised by 'sawtooth' and 'firestorm' genetic patterns, respectively; whereas luminal cancers displayed a ore heterogeneous combination of genetic patterns. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER2 and luminal cancers, respectively. PPM1D mRNA levels were significantly higher in cases harbouring PPM1D gene amplification. Silencing of PPM1D by shRNA inhibition and by a specific PPM1D phosphatase inhibitor in a panel of cell lines resulted in selective loss of viability in tumour cell lines harbouring the 17q23.2 amplification.
Conclusions: Our results demonstrate the power of aCGH analysis in unravelling the genetic profiles of specific subgroups of cancers and for the identification of novel therapeutic targets. PPM1D may be an additional therapeutic target for a subgroup of patients with HER2 and luminal breast cancers.
Monday, March 9, 2009 1:00 PM
Poster Session II # 36, Monday Afternoon