CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

Abstract

The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60-70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5-20% immunostained tumor nuclei; Po0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P ¼ 0.001) and metastases (P ¼ 0.02) and high nuclear CyclinD1 in metastases (P ¼ 0.01) predicted early cancerrelated death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.

MicroRNA-383 inhibits anchorage-independent growth and induces cell cycle arrest of glioma cells by targeting CCND1

“…Abnormal expression of CCND1 has been reported in a variety of human tumors, including breast cancer [18,19], bladder cancer [20,21], colon cancer [22,23], and glioma also included [24,25]. Growing evidence demonstrated that CCND1 is a potential therapeutic target in cancer [26,27]. In this study, we identified that CCND1 was up-regulated in glioma tissues, and found that the increased miR-383 level in glioma cells resulted in down-regulation of CCND1 protein expression.…”

Coexpression of cyclin D1 and alpha-internexin in oligodendroglial tumors

“…In the present study, we demonstrated that the cyclin D1 LI was consistently higher than the Ki-67 LI. Cyclin D1 is associated with oncogenesis of various types of tumors, including mantle cell lymphoma [24], breast cancer [25], esophageal carcinoma [26], endometrioid carcinoma [27], gastric carcinoma [28], bladder cancer [29], and cholesteatoma [30]. In brain tumors, the expression of cyclin D1 has been reported in medulloblastomas [31].…”

Cigarette smoke extract-induced proliferation of normal human urothelial cells via the MAPK/AP-1 pathway

“…Cyclin D1 is a gene that controls the cell cycle and promotes cell cycle progression through G1-phase by forming active holoenzymes with cyclin-dependent kinase (CDK)4 and CDK6, which leads to phosphorylation of retinoblastoma protein (28). Cyclin D1 overexpression has been demonstrated to be an independent adverse risk factor in metastasizing BC (29). Similarly, the PCNA gene contains AP-1 binding sites in the promoter region and thus its expression is regulated by AP-1 activity (30).…”