Przemysław Borawski, Tomasz Sirek, Agata Sirek, Nikola Zmarzły, Robert Nowakowski, Piotr Ossowski, Michał Chalcarz, Kacper Boron, Dariusz Boron, Krzysztof Bereza, Konrad Dziobek, Nina Skalska-Dziobek, Piotr Wyrobiec, Beniamin Oskar Grabarek
{"title":"Molecular crossroads: identifying MAPK proteins bridging SMAD and dopamine pathways in breast cancer.","authors":"Przemysław Borawski, Tomasz Sirek, Agata Sirek, Nikola Zmarzły, Robert Nowakowski, Piotr Ossowski, Michał Chalcarz, Kacper Boron, Dariusz Boron, Krzysztof Bereza, Konrad Dziobek, Nina Skalska-Dziobek, Piotr Wyrobiec, Beniamin Oskar Grabarek","doi":"10.1080/15384101.2025.2549097","DOIUrl":null,"url":null,"abstract":"<p><p>The transforming growth factor-beta (TGF-β)/SMAD signaling pathway, mitogen-activated protein kinase (MAPK) signaling cascade, and dopamine receptor activity are all implicated in tumor progression. This study investigates molecular interactions among these pathways, identifying MAPK proteins that bridge SMAD and dopamine signaling in the context of breast cancer pathogenesis. A cohort of 405 breast cancer patients was categorized into molecular subtypes: luminal A (<i>n</i> = 130), luminal B HER2-negative (<i>n</i> = 100), luminal B HER2-positive (<i>n</i> = 96), non-luminal HER2-positive (<i>n</i> = 36), and triple-negative breast cancer (TNBC; <i>n</i> = 43). Transcriptomic profiling using microarrays and bioinformatics-based network analysis revealed differentially expressed genes across subtypes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 11 key transcripts, and protein expression was quantified by enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) regulatory interactions were analyzed to assess post-transcriptional modulation. Among 167 differentially expressed genes, 14 were consistently altered across all subtypes. These included cell division cycle 42 (<i>CDC42</i>), KRAS proto-oncogene, GTPase (<i>KRAS</i>), and transforming growth factor beta 1 (<i>TGFB1</i>), which were upregulated, as well as fibroblast growth factor 2 (<i>FGF2</i>), fibroblast growth factor 7 (<i>FGF7</i>), and insulin-like growth factor 1 <i>(IGF1</i>), which were downregulated. miRNA analysis revealed miR-221, miR-222, and miR-16-5p as regulators of these pathways. ELISA confirmed reduced KIT, IGF1, and FGF family proteins in tumor tissues, with KRAS significantly upregulated. Protein interaction analysis highlighted key hubs linking MAPK, SMAD, and dopamine signaling. This study elucidates crucial molecular intersections between MAPK, SMAD, and dopamine pathways, identifying potential biomarkers and therapeutic targets for breast cancer.</p>","PeriodicalId":9686,"journal":{"name":"Cell Cycle","volume":" ","pages":"296-315"},"PeriodicalIF":3.4000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439586/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Cycle","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/15384101.2025.2549097","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/28 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The transforming growth factor-beta (TGF-β)/SMAD signaling pathway, mitogen-activated protein kinase (MAPK) signaling cascade, and dopamine receptor activity are all implicated in tumor progression. This study investigates molecular interactions among these pathways, identifying MAPK proteins that bridge SMAD and dopamine signaling in the context of breast cancer pathogenesis. A cohort of 405 breast cancer patients was categorized into molecular subtypes: luminal A (n = 130), luminal B HER2-negative (n = 100), luminal B HER2-positive (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (TNBC; n = 43). Transcriptomic profiling using microarrays and bioinformatics-based network analysis revealed differentially expressed genes across subtypes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 11 key transcripts, and protein expression was quantified by enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) regulatory interactions were analyzed to assess post-transcriptional modulation. Among 167 differentially expressed genes, 14 were consistently altered across all subtypes. These included cell division cycle 42 (CDC42), KRAS proto-oncogene, GTPase (KRAS), and transforming growth factor beta 1 (TGFB1), which were upregulated, as well as fibroblast growth factor 2 (FGF2), fibroblast growth factor 7 (FGF7), and insulin-like growth factor 1 (IGF1), which were downregulated. miRNA analysis revealed miR-221, miR-222, and miR-16-5p as regulators of these pathways. ELISA confirmed reduced KIT, IGF1, and FGF family proteins in tumor tissues, with KRAS significantly upregulated. Protein interaction analysis highlighted key hubs linking MAPK, SMAD, and dopamine signaling. This study elucidates crucial molecular intersections between MAPK, SMAD, and dopamine pathways, identifying potential biomarkers and therapeutic targets for breast cancer.
期刊介绍:
Cell Cycle is a bi-weekly peer-reviewed journal of high priority research from all areas of cell biology. Cell Cycle covers all topics from yeast to man, from DNA to function, from development to aging, from stem cells to cell senescence, from metabolism to cell death, from cancer to neurobiology, from molecular biology to therapeutics. Our goal is fast publication of outstanding research.