Abstract
Breast cancer is the second most common cause of cancer death in women in the United States after lung cancer and is responsible for more than 40,000 deaths each year. At the time of diagnosis, the majority of breast cancer patients have developed regional lymph node or distant metastases. Many challenges exist in the current management of metastatic breast cancer as there are fewer recognized therapeutic strategies. Therefore, a better understanding of the molecular events in the metastatic process is critical. Several reports have described correlation of hyaluronan (HA) with initiation and progression of various types of epithelial cancers. The HA synthase (HAS) isoforms encode the enzymes that produce and deposit HA while the hyaluronidase (HYAL) genes code for enzymes that degrade HA and their expression is dysregulated in various tumors as a result of transcriptional and epigenetic changes that accompany progression. In this report, we examined the expression of HAS1, HAS2 and HAS3, HYAL1 and HYAL2 in mammary tumor cell with different metastatic potential (4T1, highly metastatic; Cl66, moderately metastatic; Cl66M2, low metastatic). We observed increased expression of HAS1, HAS2 and HAS3 as well as HAYL 1 and HAYL2 in aggressive mammary tumor cells. Next we stably knocked-down HAS2 and HAS3 expression in 4T1 cells using small hairpin mRNA (sh-RNA) vectors and analyzed cell proliferation, migration, tumor growth and metastasis. We observed inhibition of in vitro cell proliferation and migration in 4T1 cells knocked-down for HAS2 (4T1-HAS2sh) and HAS3 (4T1-HAS3sh) as compared to cells transfected with vector control (4T1-controlsh). Furthermore, we observed inhibition of in vivo tumor growth and spontaneous lymph node and lung metastases in animals implanted with 4T1-HAS2sh cells as compared to 4T1-controlsh. In addition, we observed inhibition of tumor cell proliferation and neovascularization, and increased apoptosis in 4T1-shHAS2 tumors as compared to 4T1-controlsh tumors. Together, these data demonstrate an important role of HAS2 in mammary tumor growth, angiogenesis, invasion, and metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2328.