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

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.

Cervical intraepithelial neoplasia (CIN) 3‐like squamous cell carcinoma of the cervix: a review of 14 cases with comparison of E‐cadherin and cyclin D1 expression in the CIN 3‐like and infiltrative tumour elements

“…As cyclin D1 expression has also been described in the invasive component of superficially invasive (stage IA1) cervical SCCs, cyclin D1 up‐regulation may be important in both early and later stages of invasion . Similar findings have been described at the invasive front of other type of carcinomas, suggesting that cyclin D1 overexpression may be a key factor in the invasive process of many common cancers . Notably, invasion is often associated with cytoplasmic as well as nuclear cyclin D1 protein distribution, as was noted in the infiltrative SCCs in this series.…”

“…Given the morphological pattern of these tumours, with retention of a cohesive epithelial phenotype, we hypothesized that CIN 3‐like SCC might invade via mechanisms other than EMT, such as ‘collective cellular invasion’ . It is well established that EMT is characterized by down‐regulation of E‐cadherin expression, whereas stromal invasion in some tumours, including cervical SCC, is associated with the novel or increased expression of cyclin D1 . Therefore, we investigated E‐cadherin and cyclin D1 immunoreactivity in our cases comparing, where possible, CIN 3‐like and conventional invasive components in the same tumour.…”

Photodynamic Therapy Mediated by 5‐aminolevulinic Acid Promotes the Upregulation and Modifies the Intracellular Expression of Surveillance Proteins in Oral Squamous Cell Carcinoma

“…An important finding was that cyclin D1 was expressed only in the cytoplasm of the cells in the majority of the PDT specimens, whereas in the control group, it was present in the nucleus and cytoplasm. Nuclear expression of cyclin D1 is related to progression in the cell cycle and cell proliferation, whereas cytoplasmic membrane expression of cyclin D1 has been associated with tumor invasion but not necessarily with cell proliferation . Based on this result, we could not affirm that the surviving cells in the induced oral tumors would proliferate to the point of promoting the tumor regrowth, since we did not follow up the tumors after PDT treatment.…”

Tumor Heterogeneity in Endometrial Carcinoma: Practical Consequences

“…We built a variant of cyclin D1 (Ccnd1-CAAX), that remains attached to the cell membrane, sequestering this cyclin in the cytoplasm and transfecting this variant to the EEC cell lines. The tumor cells harboring Ccnd1-CAAX showed high levels of invasiveness and metastatic potential compared with the wild-type allele of Cyclin D1, confirming a role for cytoplasmic cyclin D1in invasion [17].…”