Conditional Transgenic Mouse of Hyaluronan Synthase: A Potential Model of Advanced Breast Cancer

Abstract

Hyaluronan (HA) is a polysaccharide composed of repeating GlcNAcβ(1 → 4)-GlcAβ(1 → 3) disaccharide units that is synthesized by three members of the HA synthase, HAS1, HAS2, and HAS3. HA is a major constituent of the extracellular matrix (ECM), linking proteoglycans and other binding molecules into macromolecular aggregates. HA-rich ECM provides a favorable microenvironment for cell proliferation and migration by maintaining the turgidity and hydration of tissues, and also by activating intracellular signals through interaction with cell surface receptors. Recently, HA has attracted a great deal of attention because abnormal synthesis is often associated with cancer progression; increased synthesis of HA, and in many cases, upregulation of HAS, has been linked with malignant progression in certain types of human tumors, including breast cancer, where the level of HA is considered to be a reliable prognostic indicator. Additionally, ectopic expression of HAS genes and perturbation of endogenous HA function in several cancer cell lines have both suggested that accumulated HA stimulates the growth, survival, invasion, and metastasis of cancer cells. In the following study, a transgenic mouse model that allows overexpression of murine Has2 in the mammary glands under the control of Cre recombinase was generated to further investigate the roles of HA in carcinogenesis and cancer progression (Koyama et al. 2007).