Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer.
Animals
Anticarcinogenic Agents
/ pharmacology
Breast Neoplasms
/ genetics
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Isothiocyanates
/ pharmacology
MCF-7 Cells
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplastic Stem Cells
/ drug effects
Receptors, Estrogen
/ metabolism
STAT3 Transcription Factor
/ metabolism
Signal Transduction
/ drug effects
Sulfoxides
Xenograft Model Antitumor Assays
/ methods
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
21
02
2020
accepted:
15
05
2020
revised:
13
05
2020
pubmed:
31
5
2020
medline:
15
12
2020
entrez:
31
5
2020
Statut:
ppublish
Résumé
Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Here we investigate SFX-01, a stabilised formulation of sulforaphane (SFN), for its effects on breast CSC activity in ER+ preclinical models. SFX-01 reduced mammosphere formation efficiency (MFE) of ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and aldehyde dehydrogenase (ALDH) activity of patient-derived xenograft (PDX) tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor-initiating cell frequency in secondary transplants and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months' endocrine treatment of ER+ patients (n = 68) predicted poor prognosis. Our data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.
Identifiants
pubmed: 32472077
doi: 10.1038/s41388-020-1335-z
pii: 10.1038/s41388-020-1335-z
pmc: PMC7299846
doi:
Substances chimiques
Anticarcinogenic Agents
0
Isothiocyanates
0
Receptors, Estrogen
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Sulfoxides
0
sulforaphane
GA49J4310U
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4896-4908Subventions
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/T001267/1
Pays : United Kingdom
Références
Palmieri C, Patten DK, Januszewski A, Zucchini G, Howell SJ. Breast cancer: current and future endocrine therapies. Mol Cell Endocrinol. 2014;382:695–723.
doi: 10.1016/j.mce.2013.08.001
Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377:1836–46.
doi: 10.1056/NEJMoa1701830
Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019;125:3714–28.
doi: 10.1002/cncr.32345
Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9:631–43.
doi: 10.1038/nrc2713
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Disco. 2016;6:740–53.
doi: 10.1158/2159-8290.CD-16-0095
Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3:1427–38.
pubmed: 15542782
Tripathy D, Bardia A, Sellers WR. Mechanism of action and clinical impact of ribociclib-response. Clin Cancer Res. 2017;23:5658.
doi: 10.1158/1078-0432.CCR-17-1819
Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.
doi: 10.1038/nrc2499
Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106:13820–5.
doi: 10.1073/pnas.0905718106
Simoes BM, Piva M, Iriondo O, Comaills V, Lopez-Ruiz JA, Zabalza I, et al. Effects of estrogen on the proportion of stem cells in the breast. Breast Cancer Res Treat. 2011;129:23–35.
doi: 10.1007/s10549-010-1169-4
Piva M, Domenici G, Iriondo O, Rabano M, Simoes BM, Comaills V, et al. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med. 2014;6:66–79.
doi: 10.1002/emmm.201303411
Simoes BM, O’Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, et al. Anti-estrogen resistance in human breast tumors is driven by JAG1-NOTCH4-dependent cancer stem cell activity. Cell Rep. 2015;12:1968–77.
doi: 10.1016/j.celrep.2015.08.050
Domenici G, Aurrekoetxea-Rodriguez I, Simoes BM, Rabano M, Lee SY, Millan JS, et al. A Sox2-Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells. Oncogene. 2019;38:3151–69.
doi: 10.1038/s41388-018-0656-7
Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010;16:2580–90.
doi: 10.1158/1078-0432.CCR-09-2937
Franklin SJ, Dickinson SE, Karlage KL, Bowden GT, Myrdal PB. Stability of sulforaphane for topical formulation. Drug Dev Ind Pharm. 2014;40:494–502.
doi: 10.3109/03639045.2013.768634
Dagan ID FA, Newsome PW, Baudet MP. Stabilized sulforaphane In: Organization WIP (ed). World Intellectual Property Organization, vol. WO2008091608A1, A61K 31/70 (2006.01) A61K 8/00 (2006.01) A61K 31/40 (2006.01) edn, 2008.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.
doi: 10.1016/j.stem.2007.08.014
Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 2010;140:62–73.
doi: 10.1016/j.cell.2009.12.007
Cottu P, Marangoni E, Assayag F, de Cremoux P, Vincent-Salomon A, Guyader C, et al. Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts. Breast Cancer Res Treat. 2012;133:595–606.
doi: 10.1007/s10549-011-1815-5
Eyre R, Alferez DG, Spence K, Kamal M, Shaw FL, Simoes BM, et al. Patient-derived mammosphere and xenograft tumour initiation correlates with progression to metastasis. J Mammary Gland Biol Neoplasia. 2016;21:99–109.
doi: 10.1007/s10911-016-9361-8
Clulow JA, Storck EM, Lanyon-Hogg T, Kalesh KA, Jones LH, Tate EW. Competition-based, quantitative chemical proteomics in breast cancer cells identifies new target profiles for sulforaphane. Chem Commun (Camb). 2017;53:5182–5.
doi: 10.1039/C6CC08797C
Bui QT, Im JH, Jeong SB, Kim YM, Lim SC, Kim B, et al. Essential role of Notch4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer. Cancer Lett. 2017;390:115–25.
doi: 10.1016/j.canlet.2017.01.014
Lin L, Hutzen B, Lee HF, Peng Z, Wang W, Zhao C, et al. Evaluation of STAT3 signaling in ALDH+ and ALDH+/CD44+/CD24− subpopulations of breast cancer cells. PLoS ONE. 2013;8:e82821.
doi: 10.1371/journal.pone.0082821
Sarmiento-Castro A, Caamaño-Gutiérrez E, Sims AH, James MI, Santiago-Gómez A, Eyre R, et al. A dormant sub-population expressing interleukin-1 receptor characterises anti- estrogen resistant ALDH+ breast cancer stem cells. bioRxiv 821876; 2019. https://doi.org/10.1101/821876.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31.
doi: 10.1007/s10549-009-0674-9
Turnbull AK, Arthur LM, Renshaw L, Larionov AA, Kay C, Dunbier AK, et al. Accurate prediction and validation of response to endocrine therapy in breast cancer. J Clin Oncol. 2015;33:2270–8.
doi: 10.1200/JCO.2014.57.8963
Wei W, Tweardy DJ, Zhang M, Zhang X, Landua J, Petrovic I, et al. STAT3 signaling is activated preferentially in tumor-initiating cells in claudin-low models of human breast cancer. Stem Cells. 2014;32:2571–82.
doi: 10.1002/stem.1752
Kettner NM, Vijayaraghavan S, Durak MG, Bui T, Kohansal M, Ha MJ, et al. Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer. Clin Cancer Res. 2019;25:3996–4013.
doi: 10.1158/1078-0432.CCR-18-3274
Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol. 2005;18:1917–26.
doi: 10.1021/tx0502138
Howell SJ, Campone M, Cortés J, Duhoux FP, Ross S, Morris T, et al. Final results of the STEM trial: SFX-01 in the treatment and evaluation of ER+ Her2- metastatic breast cancer (mBC). Ann Oncol. 2019;30:v122.
doi: 10.1093/annonc/mdz242.036
Parashar D, Geethadevi A, Aure MR, Mishra J, George J, Chen C, et al. miRNA551b-3p activates an oncostatin signaling module for the progression of triple-negative breast cancer. Cell Rep. 2019;29:4389–406.
doi: 10.1016/j.celrep.2019.11.085
Gaemers IC, Vos HL, Volders HH, van der Valk SW, Hilkens J. A stat-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells. J Biol Chem. 2001;276:6191–9.
doi: 10.1074/jbc.M009449200
West NR, Murphy LC, Watson PH. Oncostatin M suppresses oestrogen receptor-alpha expression and is associated with poor outcome in human breast cancer. Endocr Relat Cancer. 2012;19:181–95.
doi: 10.1530/ERC-11-0326
West NR, Murray JI, Watson PH. Oncostatin-M promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer. Oncogene. 2014;33:1485–94.
doi: 10.1038/onc.2013.105
Tawara K, Bolin C, Koncinsky J, Kadaba S, Covert H, Sutherland C, et al. OSM potentiates preintravasation events, increases CTC counts, and promotes breast cancer metastasis to the lung. Breast Cancer Res. 2018;20:53.
doi: 10.1186/s13058-018-0971-5
Alam M, Rajabi H, Ahmad R, Jin C, Kufe D. Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. Oncotarget. 2014;5:2622–34.
doi: 10.18632/oncotarget.1848
Alam M, Ahmad R, Rajabi H, Kharbanda A, Kufe D. MUC1-C oncoprotein activates ERK→C/EBPβ-mediated induction of aldehyde dehydrogenase activity in breast cancer cells. J Biol Chem. 2013;288:30829–903.
doi: 10.1074/jbc.M113.477158
Kharbanda A, Rajabi H, Jin C, Raina D, Kufe D. Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer. Mol Can Res. 2013;11:714–23.
doi: 10.1158/1541-7786.MCR-12-0668
Pitroda SP, Khodarev NN, Beckett MA, Kufe DW, Weichselbaum RR. MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment. Proc Natl Acad Sci USA. 2009;106:5837–41.
doi: 10.1073/pnas.0812029106
Clarke JD, Hsu A, Williams DE, Dashwood RH, Stevens JF, Yamamoto M, et al. Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice. Pharm Res. 2011;28:3171–9.
doi: 10.1007/s11095-011-0500-z
Shaw FL, Harrison H, Spence K, Ablett MP, Simoes BM, Farnie G, et al. A detailed mammosphere assay protocol for the quantification of breast stem cell activity. J Mammary Gland Biol Neoplasia. 2012;17:111–7.
doi: 10.1007/s10911-012-9255-3
Pearce DA, Nirmal AJ, Freeman TC, Sims AH. Continuous biomarker assessment by exhaustive survival analysis. bioRxiv 208660; 2018. https://doi.org/10.1101/208660.