Abstract 1560: Analyses of Hyaluronan (HA)-regulating genes and HA-related ECM signature in different breast cancer subtypes

Abstract

Abstract Hyaluronan (HA) is a glycosaminoglycan and one of the major extracellular matrix (ECM) components regulating cell proliferation, differentiation and motility. Given the importance of tumor-surrounding ECM, especially in drug uptake and immune cell infiltration, investigating the expression of HA-related genes in tumors and stroma and their effects on clinical outcome of different breast cancer subtypes under treatment is critical. Here we aimed to study the association of ECM and HA-related genes with disease progression, therapy response and anti-tumor immunity by analyzing gene expression datasets of breast cancer patients. We found that high stage, high grade and ER-negative/basal types of tumors have higher mRNA levels of HA synthesizing genes and lower mRNA levels of HA-degrading genes in general. Higher expression of HA synthesizing enzymes and lower expression of HA degrading enzymes (HA accumulating subset) in combination is associated with worse survival in breast cancer patients treated with systemic therapy. Among different HAS and HYAL genes, expression of HAS2, HYAL2 and PH20 (SPAM1) demonstrate the strongest association with clinical outcome in breast cancer patients treated with systemic therapies. Cumulative expression of a set of ECM-related genes cluster patients into groups with variable clinical outcome, and critically these results are recapitulated using an HA-related gene signature. Notably, although most of the patients in the HA accumulating subset are of basal subtype, there are also a relatively large fraction of luminal patients in the HA accumulating group with worse survival. Tumor and stromal specific analyses of ECM and HA-related gene signatures demonstrated that higher “tumor-specific” expression of a group of ECM-related genes predicts better therapy response that also correlates with higher immune cell infiltration. Interestingly, these patients also have higher tumor-specific levels of HA-related gene signature. On the other hand, higher “stromal-specific” expression of a different set of ECM-related genes predicts higher tumor grade that correlates with higher stromal levels of HA-related gene signature and a low immune cell infiltration. These results suggest that tumor and stromal cells might have differential expression of ECM and HA-related genes and that while tumor-specific HA levels are associated with therapy response and immune activation, stromal HA may predict higher tumor grade and lower immune cell infiltration. Overall, we demonstrated that ECM and specifically HA-related gene signatures may predict therapy response and clinical outcome in breast cancer and suggest that modulating HA may be beneficial together with systemic therapy. Citation Format: Ozge Saatci, Caglar Cekic, Ozgur Sahin. Analyses of Hyaluronan (HA)-regulating genes and HA-related ECM signature in different breast cancer subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1560.