Sulforaphane Suppresses MCF-7 Breast Cancer Cells Growth via miR-19/PTEN Axis to Antagonize the Effect of Butyl Benzyl Phthalate

Abstract Sulforaphane (SFN), a major isothiocyanate found in cruciferous vegetables, reportedly exerts extensive antitumor effects. Butyl benzyl phthalate (BBP), a widely used plasticizer, plays a crucial role in the promotion of breast cancer. In the present study, we demonstrated that SFN inhibited proliferation, induced apoptosis, and suppressed the stemness of MCF-7 cells, whereas BBP exerted the opposite effects; microRNA-19 (miR-19) plays an important role in BBP-induced cell growth and dysregulation mediated via PTEN and p21. The growth-promoting effect of BBP could be mitigated by SFN, accompanied by a reversal of altered expression of miR-19a, miR-19b, PTEN, and p21. SFN also suppressed BBP-induced binding of upregulated miR-19 with PTEN, as determined using a dual-luciferase reporter assay. Collectively, these results demonstrated, for the first time, that SFN regulates the miR-19/PTEN axis to exert protective effects against BBP-mediated breast cancer promotion, suggesting a new potential role for SFN (or SFN-rich foods) in phthalate antagonism.

[1]  Hong Yuan,et al.  Redox homeostasis modulation using theranostic AIE nanoparticles results in positive-feedback drug accumulation and enhanced drug penetration to combat drug-resistant cancer , 2022, Materials today. Bio.

[2]  P. Boor,et al.  Differential Expression of miRNAs in Trichloroethene-Mediated Inflammatory/Autoimmune Response and Its Modulation by Sulforaphane: Delineating the Role of miRNA-21 and miRNA-690 , 2022, Frontiers in Immunology.

[3]  A. Jemal,et al.  Cancer statistics, 2022 , 2022, CA: a cancer journal for clinicians.

[4]  K. Kannan,et al.  Widespread occurrence of phthalate and non-phthalate plasticizers in single-use facemasks collected in the United States. , 2021, Environment international.

[5]  A. Bishayee,et al.  Sulforaphane: A Broccoli Bioactive Phytocompound with Cancer Preventive Potential , 2021, Cancers.

[6]  Guopei Zhang,et al.  Co-exposure to BPA and DEHP enhances susceptibility of mammary tumors via up-regulating Esr1/HDAC6 pathway in female rats. , 2021, Ecotoxicology and environmental safety.

[7]  Pengfei Wu,et al.  The aggravation of allergic airway inflammation with dibutyl phthalate involved in Nrf2-mediated activation of the mast cells. , 2021, The Science of the total environment.

[8]  Hao Chen,et al.  Co-administration of sulforaphane and doxorubicin attenuates breast cancer growth by preventing the accumulation of myeloid-derived suppressor cells. , 2020, Cancer letters.

[9]  S. Andò,et al.  Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer , 2020, Oncogene.

[10]  C. Cho,et al.  Targets and mechanisms of sulforaphane derivatives obtained from cruciferous plants with special focus on breast cancer - contradictory effects and future perspectives. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[11]  P. Velasco,et al.  Glucosinolate-Degradation Products as Co-Adjuvant Therapy on Prostate Cancer in Vitro , 2019, International journal of molecular sciences.

[12]  N. Gretz,et al.  MicroRNA-365a-3p inhibits c-Rel-mediated NF-κB signaling and the progression of pancreatic cancer. , 2019, Cancer letters.

[13]  M. Mahomoodally,et al.  Combating breast cancer using combination therapy with 3 phytochemicals: Piperine, sulforaphane, and thymoquinone , 2019, Cancer.

[14]  R. Tamimi,et al.  Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Li-ting Zhou,et al.  The effect of di-2-ethylhexyl phthalate on inflammation and lipid metabolic disorder in rats. , 2019, Ecotoxicology and environmental safety.

[16]  C. Cooper,et al.  Transcriptional changes in prostate of men on active surveillance after a 12-mo glucoraphanin-rich broccoli intervention—results from the Effect of Sulforaphane on prostate CAncer PrEvention (ESCAPE) randomized controlled trial , 2019, The American journal of clinical nutrition.

[17]  J-R Zhang,et al.  Long non-coding RNA Tubulin Alpha 4B (TUBA4B) inhibited breast cancer proliferation and invasion by directly targeting miR-19. , 2019, European review for medical and pharmacological sciences.

[18]  R. Wu,et al.  miR-19 targeting of PTEN mediates butyl benzyl phthalate-induced proliferation in both ER(+) and ER(-) breast cancer cells. , 2018, Toxicology letters.

[19]  Xian-biao Shi,et al.  Overexpression of Long Noncoding RNA PTENP1 Inhibits Cell Proliferation and Migration via Suppression of miR-19b in Breast Cancer Cells , 2018, Oncology research.

[20]  Zuoren Yu,et al.  Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome , 2018, Theranostics.

[21]  M. Boerma,et al.  Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model , 2018, PloS one.

[22]  Z. Qin,et al.  Sulforaphane attenuates di‐N‐butylphthalate‐induced reproductive damage in pubertal mice: Involvement of the Nrf2‐antioxidant system , 2017, Environmental toxicology.

[23]  C. Fan,et al.  MiR‐19 regulates breast cancer cell aggressiveness by targeting profilin 1 , 2017, FEBS letters.

[24]  R. Wu,et al.  miR-19 targeting of GSK3β mediates sulforaphane suppression of lung cancer stem cells. , 2017, The Journal of nutritional biochemistry.

[25]  Tao Zhang,et al.  Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells. , 2017, Cancer letters.

[26]  Chia-Yi Hsu,et al.  Benzyl butyl phthalate decreases myogenic differentiation of endometrial mesenchymal stem/stromal cells through miR-137-mediated regulation of PITX2 , 2017, Scientific Reports.

[27]  M. Wnuk,et al.  Phytochemical-induced nucleolar stress results in the inhibition of breast cancer cell proliferation , 2017, Redox biology.

[28]  M-H Chien,et al.  Impact of low concentrations of phthalates on the effects of 17β-estradiol in MCF-7 breast cancer cells. , 2016, Taiwanese journal of obstetrics & gynecology.

[29]  E. Tsai,et al.  Benzyl butyl phthalate promotes breast cancer stem cell expansion via SPHK1/S1P/S1PR3 signaling , 2016, Oncotarget.

[30]  I. Al-Saleh,et al.  Screening of phthalate esters in 47 branded perfumes , 2015, Environmental Science and Pollution Research.

[31]  R. Wu,et al.  Curcumin Modulates miR‐19/PTEN/AKT/p53 Axis to Suppress Bisphenol A‐induced MCF‐7 Breast Cancer Cell Proliferation , 2014, Phytotherapy research : PTR.

[32]  Qun Zhou,et al.  Downregulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer , 2014, Oncogene.

[33]  T. Sun,et al.  Plasmid-based target protectors allow specific blockade of miRNA silencing activity in mammalian developmental systems , 2013, Front. Cell. Neurosci..

[34]  Xueyou Shen,et al.  Concentration and risk assessment of phthalates present in indoor air from newly decorated apartments , 2013 .

[35]  C. Chambers,et al.  Reproductive and developmental effects of phthalate diesters in females , 2013, Critical reviews in toxicology.

[36]  Fourth national report on human exposure to environmental chemicals. Updated tables, March 2021 : volume two: NHANES 2011-2016 , 2013 .

[37]  Shao-Chun Wang,et al.  n-Butyl Benzyl Phthalate Promotes Breast Cancer Progression by Inducing Expression of Lymphoid Enhancer Factor 1 , 2012, PloS one.

[38]  Shao-Chun Wang,et al.  Phthalates induce proliferation and invasiveness of estrogen receptor‐negative breast cancer through the AhR/HDAC6/c‐Myc signaling pathway , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  Hyunsuk Shim,et al.  Regulation of miR-19 to Breast Cancer Chemoresistance Through Targeting PTEN , 2011, Pharmaceutical Research.

[40]  N. Uehara,et al.  Autophagy inhibition enhances sulforaphane-induced apoptosis in human breast cancer cells. , 2010, Anticancer research.

[41]  M. Büchler,et al.  Dietary constituents of broccoli and other cruciferous vegetables: implications for prevention and therapy of cancer. , 2010, Cancer treatment reviews.

[42]  Tao Zhang,et al.  Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells , 2010, Clinical Cancer Research.

[43]  S. Lowe,et al.  miR-19 is a key oncogenic component of mir-17-92. , 2009, Genes & development.

[44]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[45]  Mutsuko Hirata-Koizumi,et al.  Potential adverse effects of phthalic acid esters on human health: a review of recent studies on reproduction. , 2008, Regulatory toxicology and pharmacology : RTP.

[46]  Michele D. Sobolewski,et al.  Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines , 2007, Molecular Cancer Therapeutics.

[47]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[48]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[49]  J. Slingerland,et al.  PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest , 2002, Nature Medicine.

[50]  J. Stanford,et al.  Fruit and vegetable intakes and prostate cancer risk. , 2000, Journal of the National Cancer Institute.

[51]  C. A. Harris,et al.  The estrogenic activity of phthalate esters in vitro. , 1997, Environmental health perspectives.