The molecular underpinning of lobular histological growth pattern: a genome-wide transcriptomic analysis of invasive lobular carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas of no special type

Authors

  • Britta Weigelt,

    Corresponding author
    1. The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
    Current affiliation:
    1. Cancer Research UK, London Research Institute, London, WC2A 3PX, UK.
    • Cancer Research UK, London Research Institute, Signal Transduction Laboratory, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
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    • These authors contributed equally to this study.

  • Felipe C Geyer,

    1. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
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    • These authors contributed equally to this study.

  • Rachael Natrajan,

    1. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
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  • Maria A Lopez-Garcia,

    1. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
    2. University Hospital Virgen del Rocio, Department of Pathology, Seville, Spain
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  • Amar S Ahmad,

    1. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
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  • Kay Savage,

    1. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
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  • Bas Kreike,

    1. The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
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  • Jorge S Reis-Filho

    Corresponding author
    1. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
    • The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
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  • No conflicts of interest were declared.

Abstract

Invasive lobular carcinoma (ILC) is the most frequent special type of breast cancer. The majority of these tumours are of low histological grade, express hormone receptors, and lack HER2 expression. The pleomorphic variant of ILCs (PLCs) is characterized by atypical cells with pleomorphic nuclei and is reported to have an aggressive clinical behaviour. Expression profiling studies have demonstrated that classic ILCs preferentially display a luminal phenotype, whereas PLCs may be of luminal, HER2 or molecular apocrine subtypes. The aims of this study were two-fold: to determine the transcriptomic characteristics of lobular carcinomas and to define the genome-wide transcriptomic differences between classic ILCs and PLCs. To define the transcriptomic characteristics of ILCs, minimizing the impact of histological grade and molecular subtype on the analysis, we subjected a series of grade- and molecular subtype-matched ILCs and invasive ductal carcinomas (IDCs) to genome-wide gene expression profiling using oligonucleotide microarrays. Hierarchical clustering analysis demonstrated that ILCs formed a separate cluster and a supervised analysis revealed that 5.8% of the transcriptionally regulated genes were significantly differentially expressed in ILCs compared to grade- and molecular subtype-matched IDCs. ILCs displayed down-regulation of E-cadherin and of genes related to actin cytoskeleton remodelling, protein ubiquitin, DNA repair, cell adhesion, TGF-beta signalling; and up-regulation of transcription factors/immediate early genes, lipid/prostaglandin biosynthesis genes, and cell migration-associated genes. Supervised analysis of classic ILCs and PLCs demonstrated that less than 0.1% of genes were significantly differentially expressed between these tumour subtypes. Our results demonstrate that ILCs differ from grade- and molecular subtype-matched IDCs in the expression of genes related to cell adhesion, cell-to-cell signalling, and actin cytoskeleton signalling. However, classic ILCs and PLCs are remarkably similar at the molecular level and should be considered as part of a spectrum of lesions. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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