Poster Presentation 28th Lorne Cancer Conference 2016

Assessing the Contribution of Interleukin(s)-6 and -11 to Progression of Inflammatory Breast Cancer (#213)

Riley J Morrow 1 2 , Cameron N Johnstone 1 2 , Matthias Ernst 1 2 , Elgene Lim 1 3 4
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  2. La Trobe University, School of Cancer Medicine, Bundoora, VIC, Australia
  3. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  4. University of New South Wales, Randwick, NSW, Australia

Background:
Inflammatory Breast Cancer (IBC) is a highly aggressive form of breast cancer, primarily diagnosed by its clinical characteristics of inflammation. Aberrant activation of the Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) signalling pathway occurs in more than 50% of primary breast cancers. The inflammatory cytokines IL-6 and IL-11 are known drivers of this pathway. However, the contribution of this pathway to IBC development is poorly understood, posing as a potential promoter of this disease.

Aims:
1. Compare the expression of components of the IL-6/JAK/STAT pathway in vitro using breast cancer cell lines of various molecular subtypes.
2. Assess whether activation of the IL-6/IL-11/JAK/STAT pathway in IBC cell lines promotes cell proliferation.
3. Determine the effects of inhibiting IL-6 signalling in IBC cell lines.
4. Assess the molecular and cellular features of IBC using human tumour samples.

Methods:
Quantitative RT-PCR (QRT-PCR) was used to assess the expression of JAK/STAT pathway components at the transcript level, and Western blot analysis to monitor the extent of active, tyrosine phosphorylated-STAT3 (pSTAT3) in vitro. Forced activation of the JAK/STAT pathway was conducted through stimulation with IL-6 and/or IL-11. MTS cell proliferation assays were used to assess cell viability following stimulation with IL-6/IL-11 +/- inhibitors. pSTAT3 and IL-6 expression was measured in human tissue via immunohistochemistry.

Results:
QRT-PCR results indicate wide expression levels of JAK/STAT signalling components, independent of breast cancer subtype. Western blot analysis confirmed that IBC cell lines showed elevated pSTAT3 expression. Stimulation with IL-6 promoted cell proliferation of IBC cell lines, which could be attenuated with various pathway targeted inhibitors. Immunohistochemistry for pSTAT3 revealed heterogeneous expression patterns in breast cancer tissue.

Conclusion:
This study suggests that IBC cell lines show elevated activation and expression of various JAK/STAT pathway components. It remains to be established in larger cohorts whether this pathway may be constitutively activated in IBC lesions and thus potentially serve as a novel therapeutic target.