Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer

Kim, Hyeon Woo; Park, Jae Eun; Baek, Minjae; Ji, Hwee Won; Yun, Sung Hwan; Jeong, Dawoon; Ham, Juyeon; Park, Sung-Bin; Lü, Xing; Kang, Hyejin; Kim, Sun Jung

doi:10.3390/cancers14051232

Cited by 15 publications

(10 citation statements)

References 45 publications

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“…In a recent investigation addressing tamoxifen resistance in breast cancer, elevated expression of MMP1 was identified as a resistance-driving gene associated with promoter methylation. 72 Genetic alteration of our HGs might contribute to abnormal expression that results in PC initiation and progression.…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis reveals upregulated extracellular matrix hub genes in pancreatic cancer: Implications for diagnosis, prognosis, immune infiltration, and therapeutic strategies

Mogal,

Jame,

Sohel

et al. 2024

Cancer Reports

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BackgroundPancreatic cancer (PC) stands out as one of the most formidable malignancies and exhibits an exceptionally unfavorable clinical prognosis due to the absence of well‐defined diagnostic indicators and its tendency to develop resistance to therapeutic interventions. The primary objective of this present study was to identify extracellular matrix (ECM)‐related hub genes (HGs) and their corresponding molecular signatures, with the intent of potentially utilizing them as biomarkers for diagnostic, prognostic, and therapeutic applications.MethodsThree microarray datasets were sourced from the NCBI database to acquire upregulated differentially expressed genes (DEGs), while MatrisomeDB was employed for filtering ECM‐related genes. Subsequently, a protein–protein interaction (PPI) network was established using the STRING database. The created network was visually inspected through Cytoscape, and HGs were identified using the CytoHubba plugin tool. Furthermore, enrichment analysis, expression pattern analysis, clinicopathological correlation, survival analysis, immune cell infiltration analysis, and examination of chemical compounds were carried out using Enrichr, GEPIA2, ULCAN, Kaplan Meier plotter, TIMER2.0, and CTD web platforms, respectively. The diagnostic and prognostic significance of HGs was evaluated through the ROC curve analysis.ResultsTen genes associated with ECM functions were identified as HGs among 131 DEGs obtained from microarray datasets. Notably, the expression of these HGs exhibited significantly (p < 0.05) higher in PC, demonstrating a clear association with tumor advancement. Remarkably, higher expression levels of these HGs were inversely correlated with the likelihood of patient survival. Moreover, ROC curve analysis revealed that identified HGs are promising biomarkers for both diagnostic (AUC > 0.75) and prognostic (AUC > 0.64) purposes. Furthermore, we observed a positive correlation between immune cell infiltration and the expression of most HGs. Lastly, our study identified nine compounds with significant interaction profiles that could potentially act as effective chemical agents targeting the identified HGs.ConclusionTaken together, our findings suggest that COL1A1, KRT19, MMP1, COL11A1, SDC1, ITGA2, COL1A2, POSTN, FN1, and COL5A1 hold promise as innovative biomarkers for both the diagnosis and prognosis of PC, and they present as prospective targets for therapeutic interventions aimed at impeding the progression PC.

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Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis reveals upregulated extracellular matrix hub genes in pancreatic cancer: Implications for diagnosis, prognosis, immune infiltration, and therapeutic strategies

Mogal,

Jame,

Sohel

et al. 2024

Cancer Reports

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“…ascertained the MMP1-dependent effect in hepatocellular carcinoma (HCC) progression via interacting with HuR and the metastasis of colorectal cancer via orchestrating the DDX3/YY1/MMP1/PI3K-AKT axis, respectively ( 26 , 27 ). It’s noteworthy that MMP1 upregulation by promoter hypomethylation has been reported with enhanced tamoxifen resistance in breast cancer ( 28 ). In this study, by conducting multifaceted cellular and molecular analyses, we for the first time identified a specific binding motif in the promoter of MMP1 for the direct transmission of the tumorigenic effect of RUNX2, which would supply novel target candidates for drug development and clinical intervention decision against the proliferation, metastasis (e.g., migration, invasion) and drug resistance of TNBC ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

RUNX2 facilitates aggressiveness and chemoresistance of triple negative breast cancer cells via activating MMP1

Wan

et al. 2022

Front. Oncol.

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Breast cancer remains the most common malignancy in women and constantly threatens the lives of patients worldwide. State-of-the-art renewal has indicated the involvement of RUNX-associated transcription factor 2 (RUNX2) in tumorigenesis and cancer progression, yet the detailed information during breast cancer is largely obscure. Herein, we took advantage of breast cancer cell lines and in vivo tumorigenicity test as well as multifaceted phenotypic analyses (e.g., RNA-sequencing, ChIP and qRT-PCR assay) to verify the pathogenic mechanism of RUNX2 in triple negative breast cancer aggressiveness and chemoresistance. Strikingly, the proliferation, migration, invasion and chemoresistance of resistant cell lines in triple negative breast cancer was effectively suppressed by RUNX2 silencing, and the in vivo tumorigenicity was significantly weakened as well. Furthermore, with the aid of transcriptomic and bioinformatic analyses, we found MMP1 was highly expressed in triple negative breast cancer (TNBC) and showed a strong correlation with the poor prognosis of the patients, which was consistent with the expression pattern of RUNX2. Finally, by conducting ChIP and qRT-PCR assessment, we verified that RUNX2 functioned via directly binding to the specific motifs in the promoter of MMP1 and thus activating the transcriptional process. Collectively, our data demonstrated the facilitating effect of RUNX2 during triple negative breast cancer progression by directly orchestrating the expression of MMP1, which supplied overwhelming new references for RUNX2-MMP1 axis serving as a novel candidate for breast cancer diagnosis and treatment.

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“…MMP-1 was also reported to be involved in tamoxifen resistance in breast cancer. Downregulation of MMP1 in tamoxifen-resistant breast cancer cells induced tamoxifen sensitivity in vitro and retarded tumor growth in vivo (98).…”

Section: Pro-tumorigenic Mmpsmentioning

confidence: 99%

Matrix metalloproteinases as therapeutic targets in breast cancer

Kwon

2023

Front. Oncol.

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Matrix metalloproteinases (MMPs) are the most prominent proteinases involved in tumorigenesis. They were initially recognized to promote tumor progression by remodeling the extracellular matrix through their proteolytic activity. However, accumulating evidence has revealed that some MMPs have protective roles in cancer progression, and the same MMP can exert opposing roles depending on the cell type in which it is expressed or the stage of cancer. Moreover, studies have shown that MMPs are involved in cancer progression through their roles in other biological processes such as cell signaling and immune regulation, independent of their catalytic activity. Despite the prognostic significance of tumoral or stromal expression of MMPs in breast cancer, their roles and molecular mechanisms in breast cancer progression remain unclear. As the failures of early clinical trials with broad-spectrum MMP inhibitors were mainly due to a lack of drug specificity, substantial efforts have been made to develop highly selective MMP inhibitors. Some recently developed MMP inhibitory monoclonal antibodies demonstrated promising anti-tumor effects in preclinical models of breast cancer. Importantly, anti-tumor effects of these antibodies were associated with the modulation of tumor immune microenvironment, suggesting that the use of MMP inhibitors in combination with immunotherapy can improve the efficacy of immunotherapy in HER2-positive or triple-negative breast cancer. In this review, the current understanding of the roles of tumoral or stromal MMPs in breast cancer is summarized, and recent advances in the development of highly selective MMP inhibitors are discussed.

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Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer

Cited by 15 publications

References 45 publications

Integrated bioinformatics analysis reveals upregulated extracellular matrix hub genes in pancreatic cancer: Implications for diagnosis, prognosis, immune infiltration, and therapeutic strategies

Integrated bioinformatics analysis reveals upregulated extracellular matrix hub genes in pancreatic cancer: Implications for diagnosis, prognosis, immune infiltration, and therapeutic strategies

RUNX2 facilitates aggressiveness and chemoresistance of triple negative breast cancer cells via activating MMP1

Matrix metalloproteinases as therapeutic targets in breast cancer

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