The role of Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) in inflammatory breast cancer (IBC)

• Author / Creator

  Zare, Alaa

• Inflammatory breast cancer (IBC) is a rare but aggressive type of breast cancer characterized by early and rapid metastasis leading to poor clinical outcomes. The tumor microenvironment (TME), including immune cells, fibroblasts and endothelial cells, has emerged as a major regulator of IBC aggressiveness, however little is known about how IBC cells may orchestrate this pro-tumorigenic milieu. This work helps us understand the importance of TME in promoting IBC metastatic behavior. Recent studies indicated that inflammatory pathways such as NF-κB concomitant with the secretion of cytokines are key elements in nurturing the IBC TME. Although NF-κB and its target genes are known to be upregulated in IBC tumor samples, its direct effect has never been studied. Herein, I show for the first time how NF-κB activation through the receptor tyrosine kinase RIPK2 can contribute to IBC progression by promoting metastatic phenotypes in cancer cells. Specifically, RIPK2 was shown to promote an inflammatory transcriptome in IBC cells leading to the secretion of factors such as IL-8, IL-6 and Activin-A. As a corollary, RIPK2 enhanced key IBC phenotypes, including angiogenic potential and metastatic growth in the lung. I also demonstrate the status of RIPK2 activity in IBC tumor samples using a special monoclonal antibody directed against the phosphorylation site Y474 utilizing IBC cell models and patient tumor samples. Elevated levels of RIPK2 phosphorylation were present in IBC samples collected at the time of diagnosis. However, chemotherapy did cause an increase in RIPK2 activity, suggesting its role in augmenting inflammation in breast tissue, which subsequently can lead to treatment resistance. Further, RIPK2 activity correlated with tumor, metastasis, and overall group stage, as well as body mass index (BMI), to indicate that RIPK2 might be a useful prognostic marker for IBC. In addition, I help identify a robust gene signature able to differentiate IBC samples from non-IBC. We report a novel IBC-specific gene signature (59 genes; G59) that achieves 100% accuracy in discovery and validation samples and remarkably only misclassified one sample in an independent dataset. G59 is independent of ER/HER2 status, molecular subtypes and is specific to untreated IBC samples, with most of the genes being enriched for plasma membrane cellular component proteins, interleukin (IL), and chemokine signaling pathways. Our finding suggests the existence of an IBC-specific molecular signature, paving the way for the identification and validation of targetable genomic drivers of IBC.In conclusion, this thesis has revealed, for the first time, a critical role for RIPK2 in the regulation of IBC phenotypes. These results suggest that RIPK2 may be an attractive target for this poorly managed disease.

• Subjects / Keywords

  • RIPK2
  • IBC
  • Breast Cancer
  • inflammation
  • Cytokine
  • Activin A
  • NF-KB

• Graduation date

  Fall 2022

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-1zvs-c749

• License

  This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.