Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1).
Invasion and metastasis are the primary causes of breast cancer mortality, and increased knowledge about the molecular mechanisms involved in these processes is highly desirable. High levels of hyaluronan in breast tumors have been correlated with poor patient survival. The involvement of hyaluronan in the early invasive phase of a clone of breast cancer cell line MDA-MB-231 that forms bone metastases was studied using an in vivo-like basement membrane model. The metastatic to bone tumor cells exhibited a 7-fold higher hyaluronan-synthesizing capacity compared with MDA-MB-231 cells predominately due to an increased expression of hyaluronan synthase 2 (HAS2). We found that knockdown of HAS2 completely suppressed the invasive capability of these cells by the induction of tissue metalloproteinase inhibitor 1 (TIMP-1) and dephosphorylation of focal adhesion kinase. HAS2 knockdown-mediated inhibition of basement membrane remodeling was rescued by HAS2 overexpression, transfection with TIMP-1 siRNA, or addition of TIMP-1-blocking antibodies. Moreover, knockdown of HAS2 suppressed the EGF-mediated induction of the focal adhesion kinase/PI3K/Akt signaling pathway. Thus, this study provides new insights into a possible mechanism whereby HAS2 enhances breast cancer invasion.
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-75124 Uppsala, Sweden.
Berit
B
Bernert
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-75124 Uppsala, Sweden.
Helena
H
Porsch
Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, SE-75124 Uppsala, Sweden. Electronic address: evi.heldin@licr.uu.se.
Paraskevi
P
Heldin
D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000378:metabolism*; D016695:Glycosyltransferases / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D016695:Glycosyltransferases; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases