Research interest
The main research interest of the group is to identify genes and signaling pathways relevant for breast cancer.
Transformation of a normal cell into a fully malignant cell requires several sequential genetic changes affecting key genes controlling various essential cellular pathways involved in growth and development. Complete knowledge of the genes and the pathways they control is essential for the development of more effective novel therapeutic strategies.
Although a large number of genes that are involved in breast and other cancers has been discovered, the picture is far from complete. Retroviral insertional mutagenesis (IM) in mouse models is one of the most efficient tools to uncover cancer genes. The aim of our laboratory is to identify and study novel genes involved in breast cancer and unravel the collaborating genetic pathways leading to breast cancer and breast cancer progression using high throughput insertional mutagenesis in mouse models.
An additional line of research concerns the biological function of cell surface associated mucins, notably episialin/MUC1 (also designated EMA, CA 15-3 antigen, CD 227), which is frequently highly upregulated in various types of cancers and has been implicated in breast cancer progression. Although we have shown that episialin/MUC1 reduces cell-cell and cell-matrix adhesion and promotes metastasis due to shielding of the adhesion receptors by its extremely elongated extra cellular domain the precise biological function of this glycoprotein still has to be elucidated.
Key publications
Theodorou V, Kimm K, Boer M, Wessels L, Theelen W, Jonkers J and Hilkens J. MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nature Genet. 2007 Apr 29; [Epub ahead of print].
Activation of Wnt3a in Mouse Mammary Tumors by Insertional Mutagenesis and Oncogenic Wnt gene Expression in MMTV induced mammary tumors and Human Breast Cancers. M.A. Kimm, V. Theodorou, M. Boer and J. Hilkens. Submitted for publication.
Hilkens J. Recent translational research: oncogene discovery by insertional mutagenesis gets a new boost. Breast Cancer Res. 2006; 8:102-6.
Theodorou V, Boer M, Weigelt B, Jonkers J, van der Valk M, Hilkens J. Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas. Oncogene. 2004; 23:6047-55
Thingstad T, Hilkens J. Tumor-host interactions regulate glucocorticoid-mediated epiglycanin expression in TA3Ha murine mammary carcinoma cells. Tumour Biol. 2003; 24:116-29
Thingstad T, Vos HL, Hilkens J. Biosynthesis and shedding of epiglycanin: a mucin-type glycoprotein of the mouse TA3Ha mammary carcinoma cell. Biochem J. 2001; 353: 33-40.
Gaemers IC, Vos HL, Volders HH, van der Valk SW, Hilkens J. A stat-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells. J Biol Chem. 2001; 276: 6191-9.
Hilkens J. and Boer M. Monoclonal antibodies against the nonmucin domain of MUC1/episialin Tumour Biol. 1998; 19: S1 67-70.
Wesseling, J., Van der Valk, S.W. and Hilkens, J. A Mechanism for Inhibition of E-Cadherin-mediated Cell-Cell Adhesion by the Membrane-associated Mucin Episialin/MUC1. Molecular Biology of the Cell, 1996; 7; 565-577.
Kwa HB, Wesseling J, Verhoeven AH, van Zandwijk N, Hilkens J. Immunoscintigraphy of small cell lung cancer xenografts with anti neural cell adhesion molecule monoclonal antibody, 123C3: Improvement of tumour uptake by internalisation. Br J Cancer. 1996; 73: 439-46.
More publications by John Hilkens on PubMed
Biographic sketch
John Hilkens studied Molecular Sciences at the Agricultural University of Wageningen and received his PhD at the University of Amsterdam in 1988 (The MAM-6 carcinoma associated epithelial sialomucin: biochemical studies and clinical application; thesis advisor: prof. dr Piet Borst).
He performed his graduate research in the laboratory of dr. J. Hilgers at the division of Tumor Biology of the Netherlands Cancer Institute. During this period he spent one and a half year in the group of dr. Frank Ruddle at the Department of Biology, Yale University, New Haven, U.S.A. where he used somatic cell genetics to study endogenous retroviral genes and genes related to retroviral infection.
He continued as a group leader at the Netherlands Cancer Institute to apply the monoclonal antibody technology to search for novel tumor associated antigens overexpressed on breast cancer cells and useful for clinical applications. He raised a large series of monoclonal antibodies against cell surface glycoproteins and used them for radioimmuno-imaging of tumors and the development of a blood test for breast cancer monitoring.
The latter work led to the CA15-3 assay, which is still widely used to date in the clinic. He cloned the Episailin/MUC1 gene and discovered that episialin/MUC1 glycoprotein (detected by the CA15-3 assay) is one of the most abundantly overexpressed glycoproteins on many cancer cells and continued to work on the biological function and regulation of this cell surface bound mucin.
During recent years he became interested in identifying novel oncogenes and oncogenic pathways involved in breast cancer by retroviral insertional mutagenesis. Among of the newly discovered genes is a novel family of secreted proteins, R-spondins, of which some members are highly oncogenic.
In 1993 he became a member of the Board of Governors of the International Association for Breast Cancer Research and since 2000 he is Secretary General of this association.
Co-workers
Vasiliki Theodorou, graduate student
Annabel Zwaagstra, graduate student
Mandy Boer, technicial staff