Anjali K. Ravi , Saradhadevi Muthukrishnan , S. Abirami , Gayathiri Gunasangkaran , Vijaya Anand Arumugam , Velayuthaprabhu Shanmugam , Marie Arockianathan Pushpam , Ashokkumar Kaliyaperumal
{"title":"维生素D3和5-aza-2 ' -脱氧胞苷对VDR甲基化和乳腺癌进展的协同作用","authors":"Anjali K. Ravi , Saradhadevi Muthukrishnan , S. Abirami , Gayathiri Gunasangkaran , Vijaya Anand Arumugam , Velayuthaprabhu Shanmugam , Marie Arockianathan Pushpam , Ashokkumar Kaliyaperumal","doi":"10.1016/j.senol.2025.100708","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><div>Breast cancer (BC) is a highly aggressive disease with limited treatment options. Calcitriol, the active form of vitamin D3, exerts anticancer effects via the vitamin D receptor (VDR), but its efficacy is often reduced by VDR promoter hypermethylation. This study investigates the role of VDR promoter hypermethylation in breast cancer and evaluates the potential of 5-Aza-2dC and vitamin D3 to restore VDR function and enhance therapeutic efficacy.</div></div><div><h3>Methods</h3><div>BALB/c mice were treated with DMBA to induce VDR promoter hypermethylation. The effects of 5-Aza-2dC and Vitamin D3 on VDR, CYP27B1, and CYP24A1 expression were evaluated to assess their impact on calcitriol signaling and BC proliferation.</div></div><div><h3>Results</h3><div>DMBA-treated mice exhibited VDR hypermethylation, increased CYP24A1, and decreased VDR and CYP27B1 expression, with significantly enhanced tumor growth. Treatment with 5-Aza-2dC reversed VDR hypermethylation, restored VDR and CYP27B1 expression, and suppressed CYP24A1, leading to reduced tumor size and higher vitamin D3 levels. Vitamin D3 pre-treatment preserved VDR and CYP27B1 expression, reduced CYP24A1, and protected against VDR methylation, decreasing tumor proliferation. Combined treatment with 5-Aza-2dC and vitamin D3 synergistically enhanced VDR demethylation, reduced CYP24A1, increased vitamin D3 levels, and significantly inhibited BC proliferation, reducing tumor size.</div></div><div><h3>Conclusion</h3><div>Reversing VDR hypermethylation with 5-Aza-2dC and vitamin D3 offers a promising strategy to overcome calcitriol resistance and improve therapeutic outcomes in BC. This combination may enhance the efficacy of vitamin D3-based therapies in BC treatment.</div></div>","PeriodicalId":38058,"journal":{"name":"Revista de Senologia y Patologia Mamaria","volume":"38 3","pages":"Article 100708"},"PeriodicalIF":0.3000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synergistic effects of vitamin D3 and 5-aza-2′-deoxycytidine on VDR methylation and breast cancer progression\",\"authors\":\"Anjali K. Ravi , Saradhadevi Muthukrishnan , S. Abirami , Gayathiri Gunasangkaran , Vijaya Anand Arumugam , Velayuthaprabhu Shanmugam , Marie Arockianathan Pushpam , Ashokkumar Kaliyaperumal\",\"doi\":\"10.1016/j.senol.2025.100708\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><div>Breast cancer (BC) is a highly aggressive disease with limited treatment options. Calcitriol, the active form of vitamin D3, exerts anticancer effects via the vitamin D receptor (VDR), but its efficacy is often reduced by VDR promoter hypermethylation. This study investigates the role of VDR promoter hypermethylation in breast cancer and evaluates the potential of 5-Aza-2dC and vitamin D3 to restore VDR function and enhance therapeutic efficacy.</div></div><div><h3>Methods</h3><div>BALB/c mice were treated with DMBA to induce VDR promoter hypermethylation. The effects of 5-Aza-2dC and Vitamin D3 on VDR, CYP27B1, and CYP24A1 expression were evaluated to assess their impact on calcitriol signaling and BC proliferation.</div></div><div><h3>Results</h3><div>DMBA-treated mice exhibited VDR hypermethylation, increased CYP24A1, and decreased VDR and CYP27B1 expression, with significantly enhanced tumor growth. Treatment with 5-Aza-2dC reversed VDR hypermethylation, restored VDR and CYP27B1 expression, and suppressed CYP24A1, leading to reduced tumor size and higher vitamin D3 levels. Vitamin D3 pre-treatment preserved VDR and CYP27B1 expression, reduced CYP24A1, and protected against VDR methylation, decreasing tumor proliferation. Combined treatment with 5-Aza-2dC and vitamin D3 synergistically enhanced VDR demethylation, reduced CYP24A1, increased vitamin D3 levels, and significantly inhibited BC proliferation, reducing tumor size.</div></div><div><h3>Conclusion</h3><div>Reversing VDR hypermethylation with 5-Aza-2dC and vitamin D3 offers a promising strategy to overcome calcitriol resistance and improve therapeutic outcomes in BC. This combination may enhance the efficacy of vitamin D3-based therapies in BC treatment.</div></div>\",\"PeriodicalId\":38058,\"journal\":{\"name\":\"Revista de Senologia y Patologia Mamaria\",\"volume\":\"38 3\",\"pages\":\"Article 100708\"},\"PeriodicalIF\":0.3000,\"publicationDate\":\"2025-06-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Revista de Senologia y Patologia Mamaria\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0214158225000441\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"OBSTETRICS & GYNECOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Revista de Senologia y Patologia Mamaria","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0214158225000441","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"OBSTETRICS & GYNECOLOGY","Score":null,"Total":0}
Synergistic effects of vitamin D3 and 5-aza-2′-deoxycytidine on VDR methylation and breast cancer progression
Introduction
Breast cancer (BC) is a highly aggressive disease with limited treatment options. Calcitriol, the active form of vitamin D3, exerts anticancer effects via the vitamin D receptor (VDR), but its efficacy is often reduced by VDR promoter hypermethylation. This study investigates the role of VDR promoter hypermethylation in breast cancer and evaluates the potential of 5-Aza-2dC and vitamin D3 to restore VDR function and enhance therapeutic efficacy.
Methods
BALB/c mice were treated with DMBA to induce VDR promoter hypermethylation. The effects of 5-Aza-2dC and Vitamin D3 on VDR, CYP27B1, and CYP24A1 expression were evaluated to assess their impact on calcitriol signaling and BC proliferation.
Results
DMBA-treated mice exhibited VDR hypermethylation, increased CYP24A1, and decreased VDR and CYP27B1 expression, with significantly enhanced tumor growth. Treatment with 5-Aza-2dC reversed VDR hypermethylation, restored VDR and CYP27B1 expression, and suppressed CYP24A1, leading to reduced tumor size and higher vitamin D3 levels. Vitamin D3 pre-treatment preserved VDR and CYP27B1 expression, reduced CYP24A1, and protected against VDR methylation, decreasing tumor proliferation. Combined treatment with 5-Aza-2dC and vitamin D3 synergistically enhanced VDR demethylation, reduced CYP24A1, increased vitamin D3 levels, and significantly inhibited BC proliferation, reducing tumor size.
Conclusion
Reversing VDR hypermethylation with 5-Aza-2dC and vitamin D3 offers a promising strategy to overcome calcitriol resistance and improve therapeutic outcomes in BC. This combination may enhance the efficacy of vitamin D3-based therapies in BC treatment.