title: Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways.
abstract: Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers.
authors.affiliation: Department of Pathology, School of Medicine, and Institute of Biomedical Science and Technology, Konkuk University Glocal Campus, Seoul, South Korea.
authors.forename: Eun Joung
authors.initials: EJ
authors.lastname: Lim
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hong
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Park
authors.forename: Youn Hee
authors.initials: YH
authors.lastname: Joung
authors.forename: Pramod
authors.initials: P
authors.lastname: Darvin
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Yoon Mi
authors.initials: YM
authors.lastname: Na
authors.forename: Tae Sook
authors.initials: TS
authors.lastname: Hwang
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Eon-Soo
authors.initials: ES
authors.lastname: Moon
authors.forename: Byung Wook
authors.initials: BW
authors.lastname: Cho
authors.forename: Kyung
authors.initials: K
authors.lastname: Do Park
authors.forename: Hak Kyo
authors.initials: HK
authors.lastname: Lee
authors.forename: Taekyu
authors.initials: T
authors.lastname: Park
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D013450:Sulfones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C025910:dimethyl sulfone; D017526:Receptor, IGF Type 1; D004121:Dimethyl Sulfoxide