Abstract
Rac1 is a member of the Ras superfamily of small guanosine triphosphatases (GTPases) that act as molecular switches to control cytoskeletal rearrangements and cell growth. Analogous to Ras, constitutively activating point mutations of Rac1 cause tumorigenic transformation of cell lines. However, there is no information about whether Rac1 is also mutated in vivo. After RT–PCR of Rac1, several clones of seven benign and 10 malignant breast cancer tissues as well as eight breast cancer cell lines were sequenced. Only single-nucleotide polymorphisms of Rac1 could be detected, and none of these corresponded to constitutively activating point mutations that have been used in cell lines for transformation. While sequencing Rac1 in breast tissues, a new Rac1 isoform with an insertion of 19 codons within the reading frame of Rac1 close to switch region II was identified and named Rac1b. The Rac1b protein acts like a fast cycling GTPase in GTP binding and hydrolysis assays. In Northern and Western blot experiments both Rac1 RNA and Rac1 protein had a significantly higher expression in breast cancer tissues compared to normal breast tissue samples. Immunohistochemical staining of Rac1 showed weak Rac1 expression in benign breast disease but high expression level in ductal carcinoma-in-situ, primary breast cancer, and lymph node metastases. In addition, breast tumor cells from patients with recurrent disease had Rac1 expression at the plasma membrane, suggesting activation of Rac1, in patients with aggressive breast cancer.
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Acknowledgements
We thank Dr A Zollner, Max-Planck Institut für Biochemie, Martinsried, Germany, for help with database analysis, Dr L Sanders, the Scripps Research Institute, Dept. of Immunology, La Jolla, CA for valuable suggestions and R Manson for critical reading of the manuscript. The authors also acknowledge the assistance of K Gauger. This research was supported by grants from the Technische Universität München (KKF 8756156 to E Lengyel and M Schmitt and KKF 8756159 to N Harbeck), the Wilhelm Sander-Stiftung (96.041.1 to E Lengyel and M Schmitt), and by funds provided by the Breast Cancer Fund of the State of California through the Breast Cancer Research Program of the University of California (2RB-0229 to U Knaus). A Schnelzer performed this study in partial fulfilment of his MD thesis and was supported by a short-term fellowship from the Boehringer Ingelheim Fonds.
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Schnelzer, A., Prechtel, D., Knaus, U. et al. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19, 3013–3020 (2000). https://doi.org/10.1038/sj.onc.1203621
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DOI: https://doi.org/10.1038/sj.onc.1203621
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