Inflammatory breast cancer is a breast cancer subtype characterized by explosive local growth and a high metastatic potential. By consequence, the prognosis for patients with IBC is dismal. Given the low incidence, IBC is a poorly characterized disease, specifically from the perspective of the associated biology. Extensive investigation of the molecular biology of IBC is needed to identify novel therapeutic markers which can result in a more adequate treatment. In addition, the molecular phenotyping of IBC can result in novel insights related to the underlying mechanisms associated with aggressive breast tumour cell behaviour. Finally, the present research aims at augmenting the watchfulness with respect to IBC, both amongst physicians and non-physicians. An increased watchfulness must result in a more precise identification of patients with IBC and a more rapid onset of adequate therapy, which in due time, must result in an improvement of the IBC-specific prognosis.
In the past, our research unit has established a genome-wide molecular profile of IBC. This molecular profile represents a collection of biological processes (e.g. augmented cell motility) and signal transduction pathways (e.g. activation of NFkB) which are differentially regulated in IBC. Follow-up studies have demonstrated that this differential regulation is, partially, caused by a discrete pattern of epigenetic changes with respect to promotor methylation and microRNA expression. Nevertheless, similar studies performed by other research groups resulted in very divergent results. In addition, it was shown that the host tissue, composed of host cells with specific genetic characteristics (“germline mutations”), of patients with IBC is also characterized by a discrete molecular profile. Recently, using mouse models, it was shown that these germline mutations are determinants of the metastatic behaviour of breast tumours. In the same context, it was demonstrated that the molecular profile of host tissue has both predictive (e.g. resistance against therapy) and prognostic (e.g. overall and metastasis-free survival) value for patients with breast cancer. The application of these molecular profiles of host tissue to IBC samples confirms the hypothesis that the genetic constitution of the host regulates the biological characteristics of IBC.
To investigate the host-specific effects with respect to the development of IBC, DNA from host tissue (white blood cells and normal breast gland tissue) from patients with IBC is collected. Using microarray technology, this DNA will be investigated for the presence of IBC-specific genetic alterations, such as mutations of single bases (Single Nucleotide Polymorphisms, SNPs) or deletions and amplifications of entire parts of the human genome (Copy Number Variations of CNVs). In combination with the existing molecular and epigenetic profile, the detection of genetic alterations in IBC can result in new insight with respect to the molecular biology of IBC (Integrated genomics-approach).
Relevant publications:
- Van Laere S, Beissbarth T, Van der Auwera I, Van den Eynden G, Trinh XB, Elst H, Van Hummelen P, van Dam P, Van Marck E, Vermeulen P, Dirix L. Relapse-free survival in breast cancer patients is associated with a gene expression signature characteristic for inflammatory breast cancer. Clin Cancer Res. 2008 Nov 15;14(22):7452-60.
- Van Laere S, Van der Auwera I, Van den Eynden G, Van Hummelen P, van Dam P, Van Marck E, Vermeulen PB, Dirix L. Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis. Br J Cancer. 2007 Oct 22;97(8):1165-74
- Van Laere SJ, Van der Auwera I, Van den Eynden GG, van Dam P, Van Marck EA, Vermeulen PB, Dirix LY. NF-kappaB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation. Br J Cancer. 2007 Sep 3;97(5):659-69.
- Van Laere SJ, Van der Auwera I, Van den Eynden GG, Elst HJ, Weyler J, Harris AL, van Dam P, Van Marck EA, Vermeulen PB, Dirix LY. Nuclear factor-kappaB signature of inflammatory breast cancer by cDNA microarray validated by quantitative real-time reverse transcription-PCR, immunohistochemistry, and nuclear factor-kappaB DNA-binding.Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3249-56.
- Van Laere SJ, Van den Eynden GG, Van der Auwera I, Vandenberghe M, Van Dam P, Van Marck EA, Van Golen KL, Vermeulen PB and Dirix LY. Identification of cell-of-origin breast tumor subtypes in Inflammatory Breast Cancer by gene expression profiling. Breast Cancer Res Treat. 2005 Oct 27;1-13.
- Van Laere S, Van der Auwera I, Van den Eynden GG, Fox SB, Bianchi F, Harris AL, van Dam P, Van Marck EA, Vermeulen PB and Dirix LY. Distinct molecular signature of inflammatory breast cancer by cDNA microarray analysis. Breast Cancer Res. Treat. 2005 Aug 22.