Abstract B84: Activation of the STAT3 pathway leads to a hyaluronan-rich microenvironment that promotes breast cancer growth and therapeutic resistance

As breast tumors form, complex interactions between the tumor cells and the surrounding stroma create a microenvironment that promotes tumor growth, resistance to therapy and recurrence. Our recent studies have focused on hyaluronan (HA), a component of the extracellular matrix that is present in the normal breast stroma but is altered at the levels of expression and fragmentation during tumor growth and progression. We have found that activation of fibroblast growth factor receptor (FGFR), which has been implicated in both triple negative and endocrine resistant breast cancers, leads to increased HA in the microenvironment. Furthermore, we have found that blocking HA synthesis decreases proliferation, migration and therapeutic resistance. Analysis of the mechanisms responsible for regulating HA synthesis revealed that FGFR-mediated HA accumulation requires activation of the signal transducer and activator of transcription 3 (STAT3) pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent HA synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and HA levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and HA synthesis are more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. Increased synthesis and fragmentation of HA are typically associated with inflammatory responses. Thus, we have expanded our studies to evaluate HA in the context of tumor-associated inflammation. Interestingly, we have found that macrophage-derived inflammatory cytokines also contribute to altered HA metabolism, linking inflammation to HA-regulated tumorigenesis. These studies suggest that tumor cells and innate immune cells cooperate to enhance the pro-tumorigenic properties of HA in the microenvironment of the developing tumor. Furthermore, we have found that HA acts through specific receptors on both tumor cells and macrophages to promote tumorigenesis, suggesting multiple mechanisms through which HA is capable of contributing to tumor formation. In conclusion, we have found that tumor cells and macrophages cooperate to induce tumor-promoting changes in the HA-containing microenvironment. Ongoing studies are focused on developing strategies that target both the tumor cells and the HA-containing microenvironment, which will ultimately lead to enhanced therapeutic efficacy for breast cancer patients. Citation Format: Laura R. Bohrer, Pavlina Chuntova, James B. McCarthy, Kathryn L. Schwertfeger. Activation of the STAT3 pathway leads to a hyaluronan-rich microenvironment that promotes breast cancer growth and therapeutic resistance. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B84. doi:10.1158/1538-7445.CHTME14-B84