Characterization of cytoplasmic cyclin D1 as a marker of invasiveness in cancer.

// Noel P. Fuste 1,4,* , Esmeralda Castelblanco 2,5,* , Isidre Felip 2,4,* , Maria Santacana 2,5 , Rita Fernandez-Hernandez 1,4 , Sonia Gatius 2,5 , Neus Pedraza 1,4 , Judit Pallares 2,5 , Tania Cemeli 1,4 , Joan Valls 3 , Marc Tarres 1,4 , Francisco Ferrezuelo 1,4 , Xavier Dolcet 2,4 , Xavier Matias-Guiu 2,4,5 and Eloi Gari 1,4 1 Department of Cell Cycle, Lleida, Catalonia, Spain 2 Department of Oncological Pathology, Lleida, Catalonia, Spain 3 Department of Biostatistics and Epidemiology Unit of the Institut de Recerca Biomedica de Lleida (IRBLLEIDA), Lleida, Catalonia, Spain 4 Department of Basic Medical Sciences at University of Lleida, Lleida, Catalonia, Spain 5 Department of Pathology and Molecular Genetics at Hospital Universitari Arnau de Vilanova, Lleida, Catalonia, Spain * These authors have contributed equally to this work Correspondence to: Eloi Gari, email: // Xavier Matias-Guiu, email: // Xavier Dolcet, email: // Keywords : cyclin D1, tissue array, cell invasion, metastasis, Pathology Section Received : December 22, 2015 Accepted : April 07, 2016 Published : April 20, 2016 Abstract Cyclin D1 (Ccnd1) is a proto-oncogen amplified in many different cancers and nuclear accumulation of Ccnd1 is a characteristic of tumor cells. Ccnd1 activates the transcription of a large set of genes involved in cell cycle progress and proliferation. However, Ccnd1 also targets cytoplasmic proteins involved in the regulation of cell migration and invasion. In this work, we have analyzed by immunohistochemistry the localization of Ccnd1 in endometrial, breast, prostate and colon carcinomas with different types of invasion. The number of cells displaying membranous or cytoplasmic Ccnd1 was significantly higher in peripheral cells than in inner cells in both collective and pushing invasion patterns of endometrial carcinoma, and in collective invasion pattern of colon carcinoma. Also, the cytoplasmic localization of Ccnd1 was higher when tumors infiltrated as single cells, budding or small clusters of cells. To evaluate cytoplasmic function of cyclin D1, we have built a variant (Ccnd1-CAAX) that remains attached to the cell membrane therefore sequestering this cyclin in the cytoplasm. Tumor cells harboring Ccnd1-CAAX showed high levels of invasiveness and metastatic potential compared to those containing the wild type allele of Ccnd1. However, Ccnd1-CAAX expression did not alter proliferative rates of tumor cells. We hypothesize that the role of Ccnd1 in the cytoplasm is mainly associated with the invasive capability of tumor cells. Moreover, we propose that subcellular localization of Ccnd1 is an interesting guideline to measure cancer outcome.