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 13 publications

(8 citation statements)

References 45 publications

(49 reference statements)

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“…In addition, RUNX2-mediated increment of MMP1 levels has been associated with chemoresistance [38]. Regarding drug resistance, MMP1 promoter hypomethylation increases tamoxifen resistance in hormone receptor-positive breast cancer [39]. Therefore, several publications support the role of MMP1 in aggressiveness in different malignancies.…”

Section: Discussionmentioning

confidence: 99%

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors

Llinàs‐Arias

Orozco

Ensenyat-Mendez

et al. 2023

Preprint

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Background Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome may contribute to matrix metalloprotease (MMP) dysregulation given their key role in invasion, which is the first step of the metastatic process.Methods We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with invasion. We stably disrupted the CCCTC-Binding Factor (CTCF) binding site of a single insulator element in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. Our findings were then also tested in a ductal carcinoma in situ (DCIS) cohort.Results We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was strongly associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability. Finally, we observed that the imbalance in the MMP expression predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01).Conclusion Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors

Llinàs‐Arias

Orozco

Ensenyat-Mendez

et al. 2023

Preprint

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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 13 publications

References 45 publications

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors

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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