Abstract
The progression of noninvasive ductal carcinoma in situ to invasive ductal carcinoma for patients with breast cancer results in a significantly poorer prognosis and is the precursor to metastatic disease. In this work, we have identified insulin-like growth factor-binding protein 2 (IGFBP2) as a potent adipocrine factor secreted by healthy breast adipocytes that acts as a barrier against invasive progression. In line with this role, adipocytes differentiated from patient-derived stromal cells were found to secrete IGFBP2, which significantly inhibited breast cancer invasion. This occurred through binding and sequestration of cancer-derived IGF-II. Moreover, depletion of IGF-II in invading cancer cells using small interfering RNAs or an IGF-II-neutralizing antibody ablated breast cancer invasion, highlighting the importance of IGF-II autocrine signaling for breast cancer invasive progression. Given the abundance of adipocytes in the healthy breast, this work exposes the important role they play in suppressing cancer progression and may help expound upon the link between increased mammary density and poorer prognosis.
| Original language | English |
|---|---|
| Article number | eadg1840 |
| Number of pages | 15 |
| Journal | Science Advances |
| Volume | 9 |
| Issue number | 28 |
| DOIs | |
| Publication status | Published - 12 Jul 2023 |
| MoE publication type | A1 Journal article-refereed |
Funding
We thank P. Laasola and J. Siivonen for technical assistance and the Ivaska lab for scientific discussion and feedback on the manuscript. We thank H. Hamidi for the illustrations and for editing the manuscript. For services, instrumentation, and expertise at Turku Bioscience (University of Turku, Turku, Finland), we would like to thank the Cell Imaging and Cytometry Core, Genome Editing Core, Turku Proteomics Facility, and Turku Centre for Disease Modelling, which are all supported by Biocenter Finland. Similarly, the Euro-BioImaging Finnish Node (Turku, Finland) and University of Turku HistoCore are also acknowledged for services, instrumentation, and expertise. The clone pENTR221-IGFBP2 was from the ORFeome library at the Genome Biology Unit core facility, supported by HiLIFE and the Faculty of Medicine, University of Helsinki, as well as Biocenter Finland. We also thank L. Polari and D. Toivola (Åbo Akademi, Turku, Finland) for FFPE healthy mouse tissue sections. Funding: This work was supported by the Finnish Cancer Institute, K. Albin Johansson Professorship (to J.I.); Academy of Finland Research project 325464 (to J.I.); Academy of Finland Centre of Excellence program 346131 (to J.I.); Cancer Foundation Finland (to J.I.); Sigrid Juselius Foundation (to J.I.); Worldwide Cancer Research 23-0123 (to J.I.); Jane and Aatos Erkko Foundation (to J.I.); Academy of Finland InFLAMES Flagship Programme 337530 (to J.I.); the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement 841973 (to J.R.W.C.); Academy of Finland postdoctoral research grant 338585 (to J.R.W.C.); Academy of Finland postdoctoral research grant 332402 (to G.F.); Sigrid Juselius Foundation (to E.P.); Academy of Finland research fellowship 323096 (to E.P.); Hospital District of Southwest Finland 11083 (to E.P.); UTUGS graduate school (to D.D.D.); and UTUGS graduate school (to O.P.). Acknowledgments:W ethankP .LaasolaandJ.SiivonenfortechnicalassistanceandtheIvaska labforscientificdiscussionandfeedbackonthemanuscript.W ethankH.Hamidiforthe illustrationsandforeditingthemanuscript.Forservices,instrumentation,andexpertiseat TurkuBioscience(UniversityofTurku,Turku,Finland),wewouldliketothanktheCellImaging andCytometryCore,GenomeEditingCore,TurkuProteomicsFacility,andTurkuCentrefor DiseaseModelling,whichareallsupportedbyBiocenterFinland.Similarly,theEuro-BioImaging FinnishNode(Turku,Finland)andUniversityofTurkuHistoC or earealsoacknowledgedfor services,instrumentation,andexpertise.TheclonepENTR221-IGFBP2wasfromtheORFeome libraryattheGenomeBiologyUnitcorefacility,supportedbyHiLIFEandtheFa culty of Medicine,UniversityofHelsinki,aswellasBiocenterFinland.W ealsothankL.Polariand D.Toiv ola (ÅboAkademi,Turku,Finland)forFFPEhealthymousetissuesections.Funding:This workwassupportedbytheFinnishCancerInstitute,K.AlbinJohanssonProfessorship(toJ.I.); AcademyofFinlandResearchproject325464(toJ.I.);AcademyofFinlandCentr eofExcellence program346131(toJ.I.);CancerFoundationFinland(toJ.I.);SigridJuseliusFoundation(toJ.I.); W orldwide CancerResearch23-0123(toJ.I.);JaneandAatosErkkoFoundation(toJ.I.);Academy of Finland InFLAMES Flagship Programme 337530 (to J.I.); the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant agreement 841973 (to J.R.W .C.); Academy of Finland postdoctoral research grant 338585 (to J.R.W .C.); Academy of Finland postdoctoral research grant 332402 (to G.F .); Sigrid Juselius Foundation (to E.P .); AcademyofFinlandresearchfellowship323096(toE.P .); HospitalDistrictofSouthwestFinland 11083(toE.P .); UTUGSgraduateschool(toD.D.D.);andUTUGSgraduateschool(toO.P .). Author contributions:J.R.W .C., D.D.D.,G.F ., andJ.K.performedtheexperiments.J.R.W .C. andG.F . undertookthedataanalysis.D.D.D.,O.P ., P .B., andP .H. providedresources.D.D.D.,G.F ., andO.P . provided methodology. J.R.W .C., E.P ., and J.I.review ed and editedthemanuscript. J.R.W .C. and J.I.wrotetheoriginaldraftofthemanuscript.E.P .andJ.I.supervisedtheproject.J.I.obtained research funding. Competing interests: The authors declare that they hav e no competing interests.Dataandmaterialsavailability:Alldataneededtoevaluatetheconclusionsinthe