Abstract PO041: Hyaluronan processing and function in the progression of breast cancer

Hyaluronan (HA) is a large, soluble, glycosaminoglycan of the extracellular matrix that has anti-inflammatory effects under physiologic conditions. However, HA is cleaved into low molecular weight (LMW) fragments under conditions of cellular or organismal stress, acting as a molecular “switch” that promotes inflammation. In breast cancer, a decrease in HA synthesis has been correlated with decreased tumor cell proliferation and migration. However, the roles of HA fragmentation in the progression of breast cancer are unknown. We predict that HA fragmentation increases during this transition, promoting inflammation through LMW HA-CD44 interactions. To test our hypothesis, the presence/absence of HA fragmentation was determined using gel electrophoresis in breast cancer cell lines. Additionally, qRT-PCR was performed to examine gene expression of the three major hyaluronan synthases (Has) 1-3 and the three major hyaluronidases (Hyal) 1, 2, and PH-20. Our data suggest as a cancerous lesion progresses, HMW HA production increases (primarily through Has2), but HA fragmentation does not occur until the tumor acquires a more aggressive phenotype (primarily through Hyal1). Following characterization of HA fragmentation and machinery within our system, we found changes in inflammatory cytokines (such as CCL2) as downstream effects of CD44 and HA synthesis inhibition. We have currently knocked out CD44 in two breast cancer cell lines using the CRISPR/Cas9 method to determine the functional relationship between CD44 and HA using an in vivo mouse model. By targeting HA-CD44 signaling associated with inflammation, new therapeutic approaches can be developed for the treatment of breast cancer. Citation Format: Patrice M. Witschen, Thomas S. Chaffee, Nicholas J. Brady, Todd P. Knutson, Rebecca S. LaRue, Sarah Munro, Lyubov Tiegs, James B. McCarthy, Andrew C. Nelson, Kathryn L. Schwertfeger. Hyaluronan processing and function in the progression of breast cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO041.