Abstract
Cyclin D1, an important regulator of cell cycle, carries out a central role in the pathogenesis of cancer determining uncontrolled cellular proliferation. In normal cells, Cyclin D1 expression levels are strictly regulated, conversely, in cancer, its activity is intensified in various manners. Different studies demonstrate that CCDN1 gene is amplified in several tumor types considering it as a negative prognostic marker of this pathology. Cyclin D1 is known for its role in the nucleus, but recent clinical studies associate the amount located in the cytoplasmic membrane with tumor invasion and metastasis. Cyclin D1 has also other functions: it governs the expression of specific miRNAs and it plays a crucial role in the tumor-stroma interactions potentiating most of the cancer hallmarks. In the present review, we will summarize the current scientific evidences that highlight the involvement of Cyclin D1 in the pathogenesis of different types of cancer, best of all in breast cancer. We will also focus on recent insights regarding the Cyclin D1 as molecular bridge between cell cycle control, adhesion, invasion, and tumor/stroma/immune-system interplay in cancer.
Highlights
Cyclin D1 is mostly known for the role played in the nucleus, as regulator of cell cycle progression.Cyclin D1 modulates the transition from G1 to S phase through its action as allosteric regulator of the cyclin-dependent kinase 4 (CDK) and CDK6
This review focuses on novel acquisitions regarding Cyclin D1 dysregulation in the cell cycle control, emerging from current research in human cancer
We recently reported that low levels of Pxn phosphorylation at Ser 83, resulting to the reduced Cyclin D1/cyclin-dependent kinase 4 (CDK4) functional interaction, led to the inhibition of mediators of membrane ruffles and actin rearrangements such as
Summary
Cyclin D1 is mostly known for the role played in the nucleus, as regulator of cell cycle progression. Further data establish that Cyclin D1 is important for the development of mammary cancers induced by different oncoproteins such as receptor tyrosine-protein kinase erbB-2 (Her2/neu) [13] and v-Ha-ras, but not those induced by c-Myc or Wnt-1 [14] These observations are consistent with data demonstrating that molecular signals targeted by Cyclin D1 overexpression cooperate with p53 loss in breast cancer initiation. BRCA1-mediated repression of estrogen receptor α (ERα)–dependent gene expression suggesting that silencing of CCND1 combined with PARP inhibitors may lead to substantial benefit for several type of cancer patients [16]. We discuss the preclinical rationale for targeting Cyclin D1/CDK in combination with current immunotherapy
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