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PARPBP is a prognostic marker and confers anthracycline resistance to breast cancer.

ABSTRACT: Background: PARPBP (PARP1 binding protein) is an important suppressor of homologous recombination during DNA repair, but the expression and function of PARPBP in breast cancer remain unclear.

Methods: PARPBP expression was analyzed in breast cancer patient samples and public datasets for its correlation with clinical outcome. The function of PARPBP in breast cancer cell proliferation and anthracycline treatment response were studied both in vitro and in vivo.

Results: PARPBP was upregulated significantly at both mRNA and protein levels in breast cancer tissues compared with normal breast tissues. PARPBP high expression group had poorer overall survival (OS) than the PARPBP low expression group. Knockdown of PARPBP suppressed breast cancer cell proliferation and colony formation while overexpression of PARPBP did the opposite. We found that transcription factor forkhead box M1 (FOXM1) could activate PARPBP expression by directly binding to the promoter of PARPBP. In addition, high expression of PARPBP related with anthracycline resistance in breast cancer. Depletion of PARPBP increased breast cancer cell apoptosis and DNA damage caused by epirubicin. Moreover, tumor xenograft experiments further demonstrated that PARPBP was involved in breast cancer anthracycline resistance.

Conclusion: Taken together, our results highlight that PARPBP is a prognostic marker and confers anthracycline resistance on breast cancer.

SUBMITTER: Chen B

PROVIDER: S-EPMC7692344 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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PARPBP is a prognostic marker and confers anthracycline resistance to breast cancer.

Chen Bo B Lai Jianguo J Dai Danian D Chen Rong R Liao Ning N Gao Guanfeng G Tang Hailin H

Therapeutic advances in medical oncology 20201124

<h4>Background</h4>PARPBP (PARP1 binding protein) is an important suppressor of homologous recombination during DNA repair, but the expression and function of PARPBP in breast cancer remain unclear.<h4>Methods</h4>PARPBP expression was analyzed in breast cancer patient samples and public datasets for its correlation with clinical outcome. The function of PARPBP in breast cancer cell proliferation and anthracycline treatment response were studied both <i>in vitro</i> and <i>in vivo</i>.<h4>Result ...[more]

PMID: 33281951

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Project description:IntroductionIncreasing evidence indicates that microRNAs (miRNAs) are important players in oncogenesis. Considering the widespread use of aromatase inhibitors (AIs) in endocrine therapy as a first-line treatment for postmenopausal estrogen receptor α-positive breast cancer patients, identifying deregulated expression levels of miRNAs in association with AI resistance is of utmost importance.MethodsTo gain further insight into the molecular mechanisms underlying the AI resistance, we performed miRNA microarray experiments using a new model of acquired resistance to letrozole (Res-Let cells), obtained by long-term exposure of aromatase-overexpressing MCF-7 cells (MCF-7aro cells) to letrozole, and a model of acquired anastrozole resistance (Res-Ana cells). Three miRNAs (miR-125b, miR-205 and miR-424) similarly deregulated in both AI-resistant cell lines were then investigated in terms of their functional role in AI resistance development and breast cancer cell aggressiveness and their clinical relevance using a cohort of 65 primary breast tumor samples.ResultsWe identified the deregulated expression of 33 miRNAs in Res-Let cells and of 18 miRNAs in Res-Ana cells compared with the sensitive MCF-7aro cell line. The top-ranked Kyoto Encyclopedia of Genes and Genomes pathways delineated by both miRNA signatures converged on the AKT/mTOR pathway, which was found to be constitutively activated in both AI-resistant cell lines. We report for the first time, to our knowledge, that ectopic overexpression of either miR-125b or miR-205, or the silencing of miR-424 expression, in the sensitive MCF-7aro cell line was sufficient to confer resistance to letrozole and anastrozole, to target and activate the AKT/mTOR pathway and to increase the formation capacity of stem-like and tumor-initiating cells possessing self-renewing properties. Increasing miR-125b expression levels was also sufficient to confer estrogen-independent growth properties to the sensitive MCF-7aro cell line. We also found that elevated miR-125b expression levels were a novel marker for poor prognosis in breast cancer and that targeting miR-125b in Res-Let cells overcame letrozole resistance.ConclusionThis study highlights that acquisition of specific deregulated miRNAs is a newly discovered alternative mechanism developed by AI-resistant breast cancer cells to achieve constitutive activation of the AKT/mTOR pathway and to develop AI resistance. It also highlights that miR-125b is a new biomarker of poor prognosis and a candidate therapeutic target in AI-resistant breast cancers.

Project description:Our purpose was to investigate whether Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) expression could be linked to prognosis in invasive breast carcinomas. NHERF1, an ezrin-radixin-moesin (ERM) binding phosphoprotein 50, is involved in the linkage of integral membrane proteins to the cytoskeleton. It is therefore believed to have an important role in cell signaling associated with changes in cell cytoarchitecture. NHERF1 expression is observed in various types of cancer and is related to tumor aggressiveness. To date the most extensive analyses of the influence of NHERF1 in cancer development have been performed on breast cancer. However, the underlying mechanism and its prognostic significance are still undefined. NHERF1 expression was studied by immunohistochemistry (IHC) in a cohort of 222 breast carcinoma patients. Association of cytoplasmic and nuclear NHERF1 expression with survival was analyzed. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Cytoplasmic NHERF1 expression was associated with negative progesterone receptor (PgR) (P=0.017) and positive HER2 expression (P=0.023). NHERF1 also showed a nuclear localization and this correlated with small tumor size (P=0.026) and positive estrogen receptor (ER) expression (P=0.010). Multivariate analysis identified large tumor size (P=0.011) and nuclear NHERF1 expression (P=0.049) to be independent prognostic variables for DFS. Moreover, the nuclear NHERF1(-)/ER(-) immunophenotype (27%) was statistically associated with large tumor size (P=0.0276), high histological grade (P=0.0411), PgR-negative tumors (P<0.0001) and high proliferative activity (P=0.0027). These patients had worse DFS compared with patients with nuclear NHERF1(+)/ER(+) tumors (75.4% versus 92.6%; P=0.010). These results show that the loss of nuclear NHERF1 expression is associated with reduced survival, and the link between nuclear NHERF1 and ER expression may serve as a prognostic marker for the routine clinical management of breast cancer patients.

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PARPBP is a prognostic marker and confers anthracycline resistance to breast cancer.

Publications

PARPBP is a prognostic marker and confers anthracycline resistance to breast cancer.

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