Abstract B66: The immunoproteasome: A point of convergence between immune response chemokine signaling and metastasis in breast cancer

Abstract

Abstract The aim of this study is to identify gene modules that mediate organ-specific metastasis in breast cancer. Epidemiological studies indicate that breast cancer subtype, based on estrogen receptor (ER) and epidermal growth factor receptor 2 (HER2/ERBB2) levels, is associated with distinct organ-specific patterns of metastasis. At a molecular level, homeostatic chemokines and their receptors have been described as one of the most important mechanisms operating in organotropic metastasis. How these seemingly independent factors might act in concert is yet to be fully understood. To address this question we adopted a novel network integration approach. We generated a metastatic driver gene set representing factors known to contribute to organotropic metastasis. Using gene expression data derived from breast cancer cells and tumor tissue, we computed the Pearson's correlation between the metastatic driver genes and all others on each microarray to develop networks, in which nodes represent genes and the edges represent the Pearson's correlation between connected genes. Given that some chemokines implicated in breast cancer metastasis are also known to play key roles in bone marrow-derived mesenchymal stem cell (BM-MSC) function during immune response, we also created a BM-MSC network. This allows us to identify parallels between BM-MSC gene expression profiles and those from breast cancer cells and tissue. This approach reveals gene modules that are conserved across, or unique to, one or more context-specific networks: thus providing insight into the influence of breast cancer subtype on immune-related chemokine signaling. Of particular interest is a gene module that links the chemokine ligands CCL2 and CCL5 with genes related to the immunoproteasome: transporter for antigen processing genes TAP1 and TAP2, and the catalytic ‘immunosubunits' PSMB8, PSMB9 and PSMB10 (the latter are implicated in immune escape). This i-proteasome gene module is conserved between the BM-MSC network and networks derived from independent datasets representing tumors that metastasized to the lung and HER2+ tumors from patients with one or more positive lymph nodes. We further explored expression patterns linking the i-proteasome gene module to known metastatic drivers. For example, the role of chemokine ligand-receptor pair CCL17-CCR4 has been previously described: CCR4 enhances the chemotactic response of breast cancer cells to the CCL17 ligand; promotes breast tumor growth and lung metastasis in mice; and is positively correlated with HER2 expression, tumor recurrence and lymph node, lung and bone metastasis. In the BM-MSC network, CCR4 is correlated, and CCL17 anti-correlated, with genes in the i-proteasome gene module. A reverse pattern is observed in tumors that metastasize to lung while both the ligand and receptor show positive correlation with the i-proteasome gene module in HER2+ tumors. In the BM-MSC network, i-proteasome genes correlate with the estrogen receptor alpha (ESR1) and are anti-correlated with the ERBB2 interacting protein gene (ERBB2IP), indicating that the i-proteasome function is likely sensitive to breast cancer subtype-related receptor levels. The Retinoic Acid Receptor Responder (Tazarotene Induced) 3 gene (RARRES3) is downregulated in breast cancer and has been shown to suppress metastasis to lung. Here, RARRES3 shows correlated expression with PSMB8 and PSMB9 in eight and seven networks respectively suggesting that the i-proteasome function is also sensitive to retinoic-related signaling. This study demonstrates a knowledge-based and data-driven approach to discovery of gene modules underlying organotropic metastasis in breast cancer. This network resource will serve as a foundation for future research into both the underlying mechanisms driving organotropic metastasis and the development of subtype-specific therapies. Citation Format: Alison M. Anderson. The immunoproteasome: A point of convergence between immune response chemokine signaling and metastasis in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B66.