Breast Cancer and Lifestyle Factors

Hoxha, Ilir; Sadiku, Fitim; Hoxha, Lot; Nasim, Midhet; Christine Buteau, Marie Anne; Grezda, Krenare; Chamberlin, Mary D.

doi:10.1016/j.hoc.2023.07.005

Cited by 7 publications

(5 citation statements)

References 72 publications

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“…Breast cancer progression involves the accumulation of aberrant changes at both genetic and epigenetic levels, which eventually lead to tumorigenesis. (3) The epigenetic regulation like DNA methylation, and histone post-translational modifications like methylation, acetylation, phosphorylation, ubiquitination, and sumoylation, alters the architecture of chromatin. These changes are well known to modulate various molecular, cellular, and biological pathways associated with breast cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Nalla,

Chatterjee,

Poyya

et al. 2024

Preprint

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Histone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 usingin silico, in vitroassays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a π-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermorein vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Nalla,

Chatterjee,

Poyya

et al. 2024

Preprint

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show abstract

“…Breast cancer (BC) is the leading cause of death by cancer in women worldwide 3 . Despite early diagnosis and treatments, such as surgery and targeted therapies, the morbidity and mortality caused by BC persist in female patients, with metastasis being the main cause of death 4 . The triple-negative BC (TNBC) subtype, accounting for 15–20% of breast cancers, is characterized by the absence of estrogen and progesterone receptors and Her2 expression 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, there are no approved targeted therapies so far. TNBC is characterized by heterogeneous, aggressive, and highly metastatic tumors that lead to poor prognosis and shorter overall survival of patients when compared to other BC subtypes 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

Truncated O-glycosylation in metastatic triple-negative breast cancer reveals a gene expression signature associated with extracellular matrix and proteolysis

Festari,

Jara,

Costa

et al. 2024

Sci Rep

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Breast cancer (BC) is the leading cause of death by cancer in women worldwide. Triple-negative (TN) BC constitutes aggressive and highly metastatic tumors associated with shorter overall survival of patients compared to other BC subtypes. The Tn antigen, a glycoconjugated structure resulting from an incomplete O-glycosylation process, is highly expressed in different adenocarcinomas, including BC. It also favors cancer growth, immunoregulation, and metastasis in TNBC. This work describes the differentially expressed genes (DEGs) associated with BC aggressiveness and metastasis in an incomplete O-glycosylated TNBC cell model. We studied the transcriptome of a TNBC model constituted by the metastatic murine 4T1 cell line that overexpresses the Tn antigen due to a mutation in one of the steps of the O-glycosylation pathway. We analyzed and compared the results with the parental wild-type cell line and with a Tn-negative cell clone that was poorly metastatic and less aggressive than the 4T1 parental cell line. To gain insight into the generated expression data, we performed a gene set analysis. Biological processes associated with cancer development and metastasis, immune evasion, and leukocyte recruitment were highly enriched among functional terms of DEGs. Furthermore, different highly O-glycosylated protein-coding genes, such as mmp9, ecm1 and ankyrin-2, were upregulated in 4T1/Tn+ tumor cells. The altered biological processes and DEGs that promote tumor growth, invasion and immunomodulation might explain the aggressive properties of 4T1/Tn+ tumor cells. These results support the hypothesis that incomplete O-glycosylation that leads to the expression of the Tn antigen, which might regulate activity or interaction of different molecules, promotes cancer development and immunoregulation.

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“…Breast and prostate cancer may be influenced by factors like physical activity, obesity, age, , family history, and oral contraceptive use. Among the diverse factors influencing cancer development and progression, epigenetic dysregulation stands out as a hallmark feature (4) . Its progression involves genetic and epigenetic changes, particularly through DNA modification like methylation and histone modifications like acetylation methylation, ubiquitination, phosphorylation, and sumoylation.…”

Section: Introductionmentioning

confidence: 99%

“…Its progression involves genetic and epigenetic changes, particularly through DNA modification like methylation and histone modifications like acetylation methylation, ubiquitination, phosphorylation, and sumoylation. These alterations affect structure of chromatin and various pathways linked to breast and prostate cancer development (4) .…”

Section: Introductionmentioning

confidence: 99%

Ellagic acid: a potential inhibitor of enhancer of zeste homolog-2 and protein arginine methyltransferase-5

Nalla,

Chatterjee,

Poyya

et al. 2024

Preprint

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Dysregulation of epigenetic processes, characterized by aberrant DNA methylation patterns and histone modifications, is a hallmark of cancer, driving its initiation, progression, and metastasis by silencing tumor suppressor genes or activating oncogenes. Perturbations in histone modifications such as H3K27me3 by EZH2 and H4R3me2s by PRMT5 play significant roles in these epigenetic alterations, disrupting normal gene expression and facilitating oncogene activation while suppressing tumor suppressor genes. Consequently, inhibitors targeting enzymes involved in DNA methylation, histone modification, or chromatin remodeling, such as PRMTs and PRC complexes, are promising anti-cancer agents, with several undergoing pre-clinical and clinical trials. Our screening of a phytochemical library revealed ellagic acid as an effective inhibitor of both EZH2 and PRMT5. Ellagic acid interacts strongly with the EZH2 and PRMT5:MEP50 complex, binding to their active sites through π-cation interactions and hydrogen bonds. Surface Plasmon Resonance study confirmed potent binding affinities of ellagic acid, with KD values of 3.28E-06 and 6.54E-05 for EZH2 and PRMT5:MEP50 respectively. In-vitro assays validated inhibitory effects on EZH2 and PRMT5:MEP50 by reducing the levels of their catalytic products H3K27me3 and H4R3me2s respectively and induction of autophagy and apoptosis. Further In-vivo studies using mouse xenografts further demonstrated significant tumor size reductions upon oral administration of ellagic acid, with decreased expression of the proliferative marker ki67 and histone repressive marks. Taken together we showed that inhibition of EZH2 and PRMT5:MEP50 by ellagic acid could be used to develop breast cancer therapeutic drug.

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Breast Cancer and Lifestyle Factors

Cited by 7 publications

References 72 publications

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo

Truncated O-glycosylation in metastatic triple-negative breast cancer reveals a gene expression signature associated with extracellular matrix and proteolysis

Ellagic acid: a potential inhibitor of enhancer of zeste homolog-2 and protein arginine methyltransferase-5

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