Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma

Ortiz, Angela B.; García, D. Escribano; Vicente, Yolanda; Palka, Magda; Bellas, Carmen; Martín, Paloma

doi:10.1371/journal.pone.0188068

Cited by 76 publications

(81 citation statements)

References 35 publications

(46 reference statements)

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“…MiR-96-5p inhibits Wnt/β-catenin signaling through its interaction with CTNND1. MMP-7, β-catenin and CyclinD1 expression are enhanced in BCa cells and promote BCa aggressiveness [13][14][15][16] . Since CTNND1 regulates Wnt/β-catenin signaling 17 we reasoned that this pathway is regulated by miR-96-5p in BCa cells.…”

Section: Mir-96-5p Expression Correlates With Bca Phenotypes To Charmentioning

confidence: 99%

MicroRNA-96-5p represses breast cancer proliferation and invasion through Wnt/β-catenin signaling via targeting CTNND1

Gao

Zhang

et al. 2020

Sci Rep

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Low miR-96-5p expression is characteristic of many cancers but its role in breast cancer (BCa) remains poorly defined. Here, the role of miR-96-5p in BC development was assessed. We demonstrate that exogenously expressing miR-96-5p inhibits the proliferative, migratory and invasive capacity of BCa cells. Mechanistically, miR-96-5p in BCa cells was found to target and downregulate catenin delta 1 (CTNND1) leading to decreased β-catenin expression, a loss of WNT11 signaling, reduced cyclin D1 levels and lower MMP7 expression. Exogenously expressing CTNND1 alleviated these effects. In summary, we are the first to reveal that miR-96-5p inhibits the proliferative, invasive and migratory phenotypes of BCa cells the targeting of CTNND1 and subsequent Wnt/β-catenin signaling. These data highlight miR-96-5p as a novel target for BC treatment. Of all life-threatening human cancer cases, breast cancer (BCa) remains the most commonly diagnosed 1. In the United States (US), nearly 330,000 new cases of BC occurred in 2017 over a third of which were invasive 2. Despite great strides to improve BCa diagnostics and therapeutics, the rates of mortality remain high with over 40000 deaths occurring in 2017 in the US alone 2. BCa cells possess a remarkable ability to metastasize to the bone marrow, the regional lymph nodes, liver, and the lungs forming a distinct tissue microenvironment (TME) that permits efficient dissemination from the site of the primary tumor 3,4. Identifying the molecular mechanisms controlling BCa progression can thus inform the design of more efficacious anti-BCa therapies. It is now well-accepted that the dysregulation of cellular MicroRNAs (miRNAs) leads to a range of pathological processes in animals and humans mediated through their ability to bind protein-coding transcripts 5. An increasing body of evidence points to the presence of a link between miRNAs to the initiation, development, and metastasis of various types of tumors, including BC 6-9. Although miR-96-5p is implicated in multiple cancers 10-12 , little is known regarding its relationship to the development and progression of BC. Here, we assessed the contribution of miR-96-5p to BCa and reveal its downregulation in BCa cells. We demonstrate that exogenously increasing miRNA-95-5p expression inhibits the proliferative and metastatic potential of BCa cells which is in part, mediated through the targeting of catenin delta 1 (CTNND1) and subsequent Wnt/β-catenin signaling. We thus highlight miR-96-5p as a novel therapeutic for much needed anti-BCa treatments. Methods Tissues and cells. We collected 155 BCa samples and non-tumor tissues. Included patients received no prior chemotherapy, immunotherapy, or radiotherapy prior to the surgery. Samples were verified as BCa for an experienced pathologist and frozen in liquid N2 prior to use. All patients signed an informed consent form. The protocol of the study was reviewed and approved by the Institutional Human Experiment and Ethic Committee of the First Affiliated Hospital of Henan University of Science...

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Section: Mir-96-5p Expression Correlates With Bca Phenotypes To Charmentioning

confidence: 99%

MicroRNA-96-5p represses breast cancer proliferation and invasion through Wnt/β-catenin signaling via targeting CTNND1

Gao

Zhang

et al. 2020

Sci Rep

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“…The cyclin D1 gene ( CCND1 ) is one of the most commonly amplified genes in human cancers and a downstream target of many oncogenic pathways. Changes in its expression have been reported to have prognostic value . Overexpression of CCND1 has been associated with the development of multiple cancers including breast cancer, melanoma, prostate cancer, lymphoma, colon cancer and parathyroid adenoma .…”

Section: Introductionmentioning

confidence: 99%

The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation

Miao

Bauer

Hufnagel

et al. 2020

Intl Journal of Cancer

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Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue-and context-dependent manner. J.D.H. and S.L. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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“…The CCND1 overexpression or CCND1 downstream pathway aberrant activation could directly promote neoplastic growth. Therefore CCND1 overexpression could be detected in different human tumors such as hepatocellular carcinoma, breast cancer and glioma …”

Section: Introductionmentioning

confidence: 99%

“…Therefore CCND1 overexpression could be detected in different human tumors such as hepatocellular carcinoma, breast cancer and glioma. [16][17][18] In this manuscript, we identified copy number amplification of GATA zinc finger domain containg 1 (GATAD1) in glioma tissues. The GATAD1 expression level is also positively correlated with its own gene amplification condition.…”

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confidence: 99%

GATAD1 gene amplification promotes glioma malignancy by directly regulating CCND1 transcription

Zhang

Gao

2019

Cancer Medicine

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Background The GATAD1 gene overexpression induced by GATAD1 amplification upregulation is detected in different human tumors. To date, the relationship between GATAD1 amplification and glioma oncogenesis and malignancy is still unknown. Methods GATAD1 gene amplification and expression were analyzed in 187 gliomas using qPCR and immunostaining. The relation of GATAD1 to patients’ prognoses was assessed via the Kaplan–Meier method. The MTT and orthotopic tumor transplantation assays were used to identify the function of GATAD1 in glioma proliferation. cDNA microarray, ChIP qPCR, EMSA and 3C were used to screen the downstream mechanism of GATAD1 regulating glioma proliferation. Results Our results indicated that GATAD1 gene amplification and GATAD1 gene expression are novel independent diagnosis biomarkers to indicate poor outcome of glioma patients. GATAD1 knockdown can remarkably suppress GBM cell proliferation both in vitro and in vivo. GATAD1 could promote CCND1 gene transcription by inducing long range chromatin architectural interaction on the CCND1 promoter. Then GATAD1 sequentially accelerates GBM cell cycle transition and proliferation via regulating CCND1. Conclusions We identify GATAD1 as a novel potential diagnosis biomarker and promising prognosis predictor in glioma patients. Functionally, we confirm GATAD1 as an epigenetic chromatin topological regulator that promotes glioma proliferation by targeting CCND1.

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Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma

Cited by 76 publications

References 35 publications

MicroRNA-96-5p represses breast cancer proliferation and invasion through Wnt/β-catenin signaling via targeting CTNND1

MicroRNA-96-5p represses breast cancer proliferation and invasion through Wnt/β-catenin signaling via targeting CTNND1

The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation

GATAD1 gene amplification promotes glioma malignancy by directly regulating CCND1 transcription

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