CCND1 and FGFR1 gene amplifications are associated with reduced benefit from aromatase inhibitors in metastatic breast cancer

Aleksakhina, Svetlana N.; Kramchaninov, Mikhail; Mikushina, Anna D.; Kubrina, S. E.; Петкау, В. В.; Ivantsov, Alexandr O.; Moiseyenko, Vladimir; Imyanitov, Evgeny N.; Iyevleva, Aglaya G.

doi:10.1007/s12094-020-02481-w

Cited by 5 publications

(6 citation statements)

References 27 publications

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“…However, our findings agree with previous studies that reported CCND1 amplification as predictive of poor prognosis in patients treated with ET, including tamoxifen (15,61) and AIs (12,14,19). However, these are not altogether unanimous; one study found that co-amplification of CCND1 and EMSY predicted tamoxifen resistance (62) whereas another found that CCND1 amplification was predictive of poor response to AIs but not tamoxifen (21). As mechanisms of ET action differ, it is possible that CCND1 amplification may contribute to resistance in some treatments but not others (63).…”

Section: Discussionsupporting

confidence: 92%

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Prognostic and Predictive Value of CCND1/Cyclin D1 Amplification in Breast Cancer With a Focus on Postmenopausal Patients: A Systematic Review and Meta-Analysis

et al. 2022

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BackgroundUp to 80% of breast cancers (BCa) are estrogen receptor positive and current treatments target the estrogen receptor (endocrine therapies) and/or CDK4/6 (CDK4/6 inhibitors). CCND1 encodes the protein cyclin D1, responsible for regulation of G1 to S phase transition in the cell cycle. CCND1 amplification is common in BCa and contributes to increased cyclin D1 expression. As there are signalling interactions between cyclin D1 and the estrogen receptor, understanding the impact of CCND1 amplification on estrogen receptor positive patients’ disease outcomes, is vital. This review aims to evaluate CCND1 amplification as a prognostic and predictive biomarker in BCa.Materials and MethodsPublications were retrieved from the databases: PubMed, MEDLINE, Embase and Cochrane library. Exclusion criteria were duplication, publication type, non-English language, in vitro and animal studies, not BCa, male BCa, premenopausal BCa, cohort size <35, CCND1 amplification not reported. Publications with cohort duplication, and inadequate recurrence free survival (RFS) and overall survival (OS) data, were also excluded. Included publications were assessed for Risk of Bias (RoB) using the Quality In Prognosis Studies tool. Statistical analyses (Inverse Variance and Mantel-Haenszel) were performed in Review Manager. The PROSPERO registration number is [CRD42020208179].ResultsCCND1 amplification was significantly associated with positive estrogen receptor status (OR:1.70, 95% CI:1.19-2.43, p = 0.004) and cyclin D1 overexpression (OR: 5.64, 95% CI: 2.32-13.74, p=0.0001). CCND1 amplification was significantly associated with shorter RFS (OR: 1.64, 95% CI: 1.13-2.38, p = 0.009), and OS (OR: 1.51, 95% CI: 1.19-1.92, p = 0.0008) after removal of studies with a high RoB. In endocrine therapy treated patients specifically, CCND1 amplification predicted shorter RFS (HR: 2.59, 95% CI: 1.96-3.41, p < 0.00001) and OS (HR: 1.59, 95% CI: 1.00-2.49, p = 0.05) also after removal of studies with a high RoB.ConclusionWhile a lack of standardised approach for the detection of CCND1 amplification is to be considered as a limitation, CCND1 amplification was found to be prognostic of shorter RFS and OS in BCa. CCND1 amplification is also predictive of reduced RFS and OS in endocrine therapy treated patients specifically. With standardised methods and cut offs for the detection of CCND1 amplification, CCND1 amplification would have potential as a predictive biomarker in breast cancer patients.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42020208179.

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Section: Discussionsupporting

confidence: 92%

“…Some studies have shown significant association between CCND1 amplification and poor aromatase inhibitor (AI) (18,19) and tamoxifen response (19), whilst another study has shown no association with tamoxifen response (20). Yet, another study suggested CCND1 was predictive of resistance to aromatase inhibitors but not to tamoxifen (21).…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Predictive Value of CCND1/Cyclin D1 Amplification in Breast Cancer With a Focus on Postmenopausal Patients: A Systematic Review and Meta-Analysis

et al. 2022

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“…The process of acquired tamoxifen resistance has been considered intricate and could not be explained by a single biological mechanism. Accumulating evidence 5,6 . has confirmed the hypothesis that tamoxifen resistance is caused by genetic alterations in epithelial tumor cells.…”

Section: Introductionmentioning

confidence: 84%

“…The cells in each group were pretreated with serum‐free and phenol‐free DMEM medium for 24 h. Then, the cell number was adjusted to 5 × 10 5 /ml, and 500 μl of DMEM medium containing 5% fetal bovine serum was added into the lower chamber of the Transwell chamber. After the treatment, 5 × 10 4 cells were added to the upper chamber of the Transwell chamber and cultured at 37°C for 36 h in an incubator saturated with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Role of β1‐integrin in promoting cell motility and tamoxifen resistance of human breast cancer MCF‐7 cells

Yang

Chen

et al. 2022

Asia-Pac J Clncl Oncology

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BackgroundThe mechanism of acquired resistance of tamoxifen in endocrine therapy of breast cancer is not fully understood. In this study, we investigated the genomic changes in acquired tamoxifen‐resistant cell lines.MethodsTamoxifen‐resistant subclones (MCF‐7R) derived from parent MCF‐7 cells, which is an ER(+) breast cancer cell line, cultured with 4‐hydrotamoxifen more than 6 months were used to obtain genomic alterations. Cell growth, microarray, and quantitative real‐time PCR (q‐RTPCR) assays were conducted. Additionally, the ITGB1 function was investigated in MCF‐7R cells and MCF‐7R ITGB1‐silenced subclones using MTT and Transwell assays. Online pathway analysis was performed to assess the genetic characteristics of tamoxifen resistance.ResultsThe gene expression profile of the tamoxifen‐resistant cell line was considerably changed compared to the tamoxifen‐sensitive cell line. Of 4102 genes with altered expressions, 1986 genes were upregulated, whereas 2116 were downregulated. The ITGB1 expression in MCF‐7R cells was higher than that in MCF‐7 cells. Interestingly, ITGB1 silencing partially rescued the sensitivity of MCF‐7R cells to tamoxifen and reduced their motility. The activation of the β1‐integrin signaling pathway was probably responsible for this phenomenon.ConclusionsOur data confirm the presence of alterations in the genes of tamoxifen‐resistance breast cancer cells. ITGB1 probably partially contributes to tamoxifen resistance and cell motility via the β1‐integrin signaling pathway. Thus, ITGB1 may be a potential target for the improvement of anti‐hormone therapy reaction in ER(+) breast cancer patients.

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“…FGFRs are aberrantly activated in cholangiocarcinoma (CCA) and most of the alterations involve the FGFR2 coding gene [4]. Upregulation of FGFR1 contributes to the progression and resistance in lung and breast cancer [5][6][7][8]. FGFR3 fusion with transforming acidic coiledcoil-containing protein 3 (TACC3) (FGFR-TACC3) has been characterized and correlated with a more aggressive phenotype in malignancies such as glioblastoma and head and neck cancers, for which no effective therapeutic option is still available [9].…”

Section: Introductionmentioning

confidence: 99%

Targeting FGFRs by pemigatinib induces G1 phase cell cycle arrest, cellular stress and upregulation of tumor suppressor microRNAs

Pace,

Scirocchi,

Napoletano

et al. 2023

J Transl Med

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Background Fibroblast growth factor receptor (FGFR) gene family alterations are found in several cancers, indicating their importance as potential therapeutic targets. The FGFR-tyrosine kinase inhibitor (TKI) pemigatinib has been introduced in the treatment of advanced cholangiocarcinoma and more recently for relapsed or refractory myeloid/lymphoid neoplasms with FGFR2 and FGFR1 rearrangements, respectively. Several clinical trials are currently investigating the possible combination of pemigatinib with immunotherapy. In this study, we analyzed the biological and molecular effects of pemigatinib on different cancer cell models (lung, bladder, and gastric), which are currently objective of clinical trial investigations. Methods NCI-H1581 lung, KATO III gastric and RT-112 bladder cancer cell lines were evaluated for FGFR expression by qRT-PCR and Western blot. Cell lines were treated with Pem and then characterized for cell proliferation, apoptosis, production of intracellular reactive oxygen species (ROS), and induction of senescence. The expression of microRNAs with tumor suppressor functions was analyzed by qRT-PCR, while modulation of the proteins coded by their target genes was evaluated by Western blot and mRNA. Descriptive statistics was used to analyze the various data and student’s t test to compare the analysis of two groups. Results Pemigatinib exposure triggered distinct signaling pathways and reduced the proliferative ability of all cancer cells, inducing G1 phase cell cycle arrest and strong intracellular stress resulting in ROS production, senescence and apoptosis. Pemigatinib treatment also caused the upregulation of microRNAs (miR-133b, miR-139, miR-186, miR-195) with tumor suppressor functions, along with the downregulation of validated protein targets with oncogenic roles (c-Myc, c-MET, CDK6, EGFR). Conclusions These results contribute to clarifying the biological effects and molecular mechanisms mediated by the anti-FGFR TKI pemigatinib in distinct tumor settings and support its exploitation for combined therapies.

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CCND1 and FGFR1 gene amplifications are associated with reduced benefit from aromatase inhibitors in metastatic breast cancer

Cited by 5 publications

References 27 publications

Prognostic and Predictive Value of CCND1/Cyclin D1 Amplification in Breast Cancer With a Focus on Postmenopausal Patients: A Systematic Review and Meta-Analysis

Prognostic and Predictive Value of CCND1/Cyclin D1 Amplification in Breast Cancer With a Focus on Postmenopausal Patients: A Systematic Review and Meta-Analysis

Role of β1‐integrin in promoting cell motility and tamoxifen resistance of human breast cancer MCF‐7 cells

Targeting FGFRs by pemigatinib induces G1 phase cell cycle arrest, cellular stress and upregulation of tumor suppressor microRNAs

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