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ARTICLE

Research on Clinical Effectiveness of Aspirin for Treating Breast Cancer and Cell Protein Biomarkers on Aspirin Treatment in Drug-Resistant Estrogen Receptor-Positive Breast Cancer Cells

Junwei Cui¹, Minghua Li², Ruifang Pang^2,*, Yinhua Liu^1,*

1 Breast Disease Center, Peking University First Hospital, Peking University, Beijing, China
2 Institute of Precision Medicine, Peking University Shenzhen Hospital, Peking University, Shenzhen, China

* Corresponding Authors: Ruifang Pang. Email: ; Yinhua Liu. Email:

(This article belongs to the Special Issue: Biomarkers for Breast Cancer Diagnosis and Treatment Selection: from Basic Research to Practice)

Oncologie 2022, 24(4), 743-768. https://doi.org/10.32604/oncologie.2022.025419

Received 12 July 2022; Accepted 09 September 2022; Issue published 31 December 2022

Abstract

Background: Aspirin (ASA) has been reported to have an antitumor effect but the role of ASA in the prevention and treatment of breast cancer (BC) is still controversial. This study aimed to identify clinical effectiveness of ASA in the treatment of BC and explore the antitumor target proteins of ASA that may be involved in overcoming tamoxifen resistance in estrogen receptor (ER)-positive BC cells. Materials and Methods: Randomized controlled trials (RCTs) of ASA in the treatment of BC were queried from the databases, including PubMed, Web of Science, Cochrane Library, WanFang, and Chinese National Knowledge Infrastructure. According to the quality standard recommended in the Newcastle-Ottawa Scale (NOS), the outcome indexes were analyzed by RevMan 5.3 and Stata 12.0 software. Cell culture experiments were performed to explore the effect of tamoxifen combined with ASA on the proliferation of ER-positive BC cell lines MCF-7 and MCF-7/TAM. Cell cytotoxicity was determined by the 3-(4, 5-di-2-yl)-2, 5-ditetrazolium bromide (MTT) assay. A quantitative proteomic analysis was conducted between the control and experimental groups to identify differentially expressed proteins (DEPs). Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used for bioinformatic analysis of DEPs. The protein expression in patients of ER-positive BC was analyzed by immunochemistry (IHC). Results: Nine RCTs including 162,381 patients were selected for this study. The meta-analysis revealed that daily ASA use, as compared with its non-use, was associated with a decreased risk of BC death: relative risk (RR) = 0.83%, 95% CI [0.73, 0.94], Z = 2.89, P = 0.004 (P < 0.05). Cell culture experiments showed that tamoxifen combined with ASA can drastically inhibit the cell growth of MCF-7 and MCF-7/TAM cells more than the administration of tamoxifen alone (P < 0.05). Fifty-seven DEPs were up-regulated, while eighty-five DEPs were down-regulated in MCF-7/TAM cells after the ASA combination treatment. Several GO terms were significantly enriched, such as neutrophil degranulation, retinal metabolic process, sterol biosynthetic process, and prostaglandin metabolic process. KEGG pathway enrichment analysis also verified three associated pathways including metabolic pathways, chemical carcinogenesis-reactive oxygen species, and biosynthesis of amino acids. In ER-positive BC patients with Ki67 > 20%, the positive expression of one significantly DEP MYC was much higher than in BC patients with Ki67 ≤ 20% (40.91% vs. 12.50%, P < 0.05). There was no significant difference in MYC protein expression among the other subgroups (P > 0.05). Conclusions: Our results show that ASA has a clinical value in the treatment of BC. ASA could overcome tamoxifen resistance in ER-positive BC cells through some key proteins, which may be potential therapeutic targets for patients with tamoxifen resistance.

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