Widespread screening mammography programmes mean that ductal carcinoma in situ (DCIS), a pre-invasive breast lesion, is now more frequently diagnosed. However, not all diagnosed DCIS lesions progress to invasive breast cancer, which presents a dilemma for clinicians. As such, there is much interest in studying DCIS in the laboratory, in order to help understand more about its biology and determine the characteristics of those that progress to invasion. Greater knowledge would lead to targeted and better DCIS treatment. Here, we outline some of the models available to study DCIS, with a particular focus on animal-free systems.
BleyerA. & WelchH.G. (2012). Effect of three decades of screening mammography on breast-cancer incidence. New England Journal of Medicine367, 1998–2005.
2.
Independent UKPoBCS (2012). The benefits and harms of breast cancer screening: An independent review. The Lancet380, 1778–1786.
3.
BijkerN., MeijnenP., PeterseJ.L., BogaertsJ., Van HoorebeeckI., JulienJ-P., GennaroM., RouanetP., AvrilA., FentimanI.S., BartelinkH. & RutgersE.J.T. (2006). Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: Ten-year results of European Organisation for Research and Treatment of Cancer Randomized Phase III Trial 10853 — A study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Journal of Clinical Oncology24, 3381–3387.
4.
SoumianS., VergheseE.T., BoothM., SharmaN., ChaudhriS., BradleyS., UmranikarS., Millican-SlaterR.A., HanbyA.M. & FrancisA. (2013). Concordance between vacuum assisted biopsy and postoperative histology: Implications for the proposed Low Risk DCIS Trial (LORIS). European Journal of Surgical Oncology39, 1337–1340.
5.
WitkiewiczA.K., RivadeneiraD.B., ErtelA., KlineJ., HyslopT., SchwartzG.F., FortinaP. & KnudsenE.S. (2011). Association of RB/p16-pathway perturbations with DCIS recurrence: Dependence on tumor versus tissue microenvironment. American Journal of Pathology179, 1171–1178.
6.
AllenM.D., ThomasG.J., ClarkS., DawoudM.M., VallathS., PayneS.J., GommJ.J., DregerS.A., DickinsonS., EdwardsD.R., PenningtonC.J., SestakI., CuzickJ., MarshallJ.F., HartI.R. & JonesJ.L. (2014). Altered microenvironment promotes progression of preinvasive breast cancer: Myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. Clinical Cancer Research20, 344–357.
7.
HebnerC., WeaverV.M. & DebnathJ. (2008). Modeling morphogenesis and oncogenesis in three-dimensional breast epithelial cultures. Annual Review of Pathology3, 313–339.
8.
DebnathJ., MuthuswamyS.K. & BruggeJ.S. (2003). Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods30, 256–268.
9.
TaraseviciuteA., VincentB.T., SchedinP. & JonesP.L. (2010). Quantitative analysis of three-dimensional human mammary epithelial tissue architecture reveals a role for tenascin-C in regulating c-met function. American Journal of Pathology176, 827–838.
10.
LeeG.Y., KennyP.A., LeeE.H. & BissellM.J. (2007). Three-dimensional culture models of normal and malignant breast epithelial cells. Nature Methods4, 359–365.
11.
NashC.E., MavriaG., BaxterE.W., HollidayD.L., TomlinsonD.C., TreanorD., NovitskayaV., BerditchevskiF., HanbyA.M. & SpeirsV. (2015). Development and characterisation of a 3D multicellular in vitro model of normal human breast: A tool for cancer initiation studies. Oncotarget6, 13, 731–13, 741.
12.
BentonG., ArnaoutovaI., GeorgeJ., KleinmanH.K. & KoblinskiJ. (2014). Matrigel: From discovery and ECM mimicry to assays and models for cancer research. Advanced Drug Delivery Reviews 79–80, 3–18.
13.
FarnieG., JohnsonR.L., WilliamsK.E., ClarkeR.B. & BundredN.J. (2014). Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS). Cell Cycle13, 418–425.
14.
MillerF.R., SantnerS.J., TaitL. & DawsonP.J. (2000). MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ. Journal of the National Cancer Institute92, 1185–1186.
15.
HuM., YaoJ., CarrollD.K., WeremowiczS., ChenH., CarrascoD., RichardsonA., VioletteS., NikolskayaT., NikolskyY., BauerleinE.L., HahnW.C., GelmanR.S., AllredC., BissellM.J., SchnittS. & PolyakK. (2008). Regulation of in situ to invasive breast carcinoma transition. Cancer Cell13, 394–406.
16.
BehbodF., KittrellF.S., LaMarcaH., EdwardsD., KerbawyS., HeestandJ.C., YoungE., MukhopadhyayP., YehH-W., AllredD.C., HuM., PolyakK., RosenJ.M. & MedinaD. (2009). An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ. Breast Cancer Research11, R66–R66.
17.
ValdezK.E., FanF., SmithW., AllredD.C., MedinaD. & BehbodF. (2011). Human primary ductal carcinoma in situ (DCIS) subtype-specific pathology is preserved in a mouse intraductal (MIND) xenograft model. Journal of Pathology225, 565–573.
18.
VisvaderJ.E. (2009). Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes & Development23, 2563–2577.
19.
MedinaD., EdwardsD., KittrellF., LeeS. & AllredD.C. (2012). Intra-mammary ductal transplantation: A tool to study premalignant progression. Journal of Mammary Gland Biology & Neoplasia17, 131–133.
20.
WeigeltB., GhajarC.M. & BissellM.J. (2014). The need for complex 3D culture models to unravel novel pathways and identify accurate biomarkers in breast cancer. Advanced Drug Delivery Reviews 69–70, 42–51.
21.
SungK.E., SuX., BerthierE., PehlkeC., FriedlA. & BeebeD.J. (2013). Understanding the impact of 2D and 3D fibroblast cultures on in vitro breast cancer models. PLoS One8, e76373.
22.
VergheseE.T., DruryR., GreenC.A., HollidayD.L., LuX., NashC., SpeirsV., ThorneJ.L., ThygesenH.H., ZougmanA., HullM.A., HanbyA.M. & HughesT.A. (2013). MiR-26b is down-regulated in carcinoma-associated fibroblasts from ERpositive breast cancers leading to enhanced cell migration and invasion. Journal of Pathology231, 388–399.
23.
BochetL., LehuedeC., DauvillierS., WangY.Y., DiratB., LaurentV., DrayC., GuietR., Maridonneau-PariniI., Le GonidecS., CoudercB., EscourrouG., ValetP. & MullerC. (2013). Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Research73, 5657–5668.
24.
OlsenC.J., MoreiraJ., LukanidinE.M. & AmbartsumianN.S. (2010). Human mammary fibroblasts stimulate invasion of breast cancer cells in a three-dimensional culture and increase stroma development in mouse xenografts. BMC Cancer10, 444.
25.
WangX., SunL., MaffiniM.V., SotoA., SonnenscheinC. & KaplanD.L. (2010). A complex 3D human tissue culture system based on mammary stromal cells and silk scaffolds for modeling breast morphogenesis and function. Biomaterials31, 3920–3929.
26.
WangX. & KaplanD.L. (2012). Hormone-responsive 3D multicellular culture model of human breast tissue. Biomaterials33, 3411–3420.
27.
CampbellJ.J., BotosL.A., SargeantT.J., DavidenkoN., CameronR.E. & WatsonC.J. (2014). A 3D in vitro co-culture model of mammary gland involution. Integrative Biology6, 618–626.
28.
WangX., ZhangX., SunL., SubramanianB., MaffiniM.V., SotoA., SonnenscheinC. & KaplanD.L. (2009). Preadipocytes stimulate ductal morphogenesis and functional differentiation of human mammary epithelial cells on 3D silk scaffolds. Tissue Engineering Part A15, 3087–3098.
29.
Correa de SampaioP., AuslaenderD., KrubasikD., FaillaA.V., SkepperJ.N., MurphyG. & EnglishW.R. (2012). A heterogeneous in vitro three dimensional model of tumour-stroma interactions regulating sprouting angiogenesis. PLoS One7, e30753.
30.
Rama-EsendagliD., EsendagliG., YilmazG. & GucD. (2014). Spheroid formation and invasion capacity are differentially influenced by co-cultures of fibroblast and macrophage cells in breast cancer. Molecular Biology Reports41, 2885–2892.
31.
HollidayD.L., BrouiletteK.T., MarkertA., GordonL.A. & JonesJ.L. (2009). Novel multicellular organotypic models of normal and malignant breast: Tools for dissecting the role of the microenvironment in breast cancer progression. Breast Cancer Research11, R3.
32.
FarnieG., ClarkeR.B., SpenceK., PinnockN., BrennanK., AndersonN.G. & BundredN.J. (2007). Novel cell culture technique for primary ductal carcinoma in situ: Role of Notch and epidermal growth factor receptor signaling pathways. Journal of the National Cancer Institute99, 616– 627.
33.
DontuG., JacksonK.W., McNicholasE., KawamuraM.J., AbdallahW.M. & WichaM.S. (2004). Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Research6, R605–R615.
34.
WenzelC., OttoS., PrechtlS., ParczykK. & SteigemannP. (2015). A novel 3D high-content assay identifies compounds that prevent fibroblast invasion into tissue surrogates. Experimental Cell Research. [E-pub ahead of print.]
35.
SinghM., CloseD.A., MukundanS., JohnstonP.A. & SantS. (2015). Production of uniform 3D microtumors in hydrogel microwell arrays for measurement of viability, morphology, and signaling pathway activation. Assay & Drug Development Technologies. [E-pub ahead of print.]
36.
SirenkoO., MitloT., HesleyJ., LukeS., OwensW. & CromwellE.F. (2015). High-content assays for characterizing the viability and morphology of 3D cancer spheroid cultures. Assay & Drug Development Technologies13, 402–414.
37.
SackmannE.K., FultonA.L. & BeebeD.J. (2014). The present and future role of microfluidics in biomedical research. Nature, London507, 181–189.
38.
SungK.E. & BeebeD.J. (2014). Microfluidic 3D models of cancer. Advanced Drug Delivery Reviews 79–80, 68–78.
39.
van DuinenV., TrietschS.J., JooreJ., VultoP. & HankemeierT. (2015). Microfluidic 3D cell culture: From tools to tissue models. Current Opinion in Biotechnology35, 118–126.
40.
BischelL.L., BeebeD.J. & SungK.E. (2015). Microfluidic model of ductal carcinoma in situ with 3D, organotypic structure. BMC Cancer15, 12.
41.
ChoiY., HyunE., SeoJ., BlundellC., KimH.C., LeeE., LeeS.H., MoonA., MoonW.K. & HuhD. (2015). A microengineered pathophysiological model of early-stage breast cancer. Lab on a Chip15, 3350–3357.
42.
SungK.E., YangN., PehlkeC., KeelyP.J., EliceiriK.W., FriedlA. & BeebeD.J. (2011). Transition to invasion in breast cancer: A microfluidic in vitro model enables examination of spatial and temporal effects. Integrative Biology3, 439–450.
43.
JeonJ.S., BersiniS., GilardiM., DubiniG., CharestJ.L., MorettiM. & KammR.D. (2015). Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proceedings of the National Academy of Sciences of the USA112, 214–219.
44.
SunL., WangD., ZubovitsJ.T., YaffeM.J. & ClarkeG.M. (2009). An improved processing method for breast whole-mount serial sections for three-dimensional histopathology imaging. American Journal of Clinical Pathology131, 383–392.
45.
MarchioC., SapinoA., ArisioR. & BussolatiG. (2006). A new vision of tubular and tubulo-lobular carcinomas of the breast, as revealed by 3-D modelling. Histopathology48, 556–562.
46.
NortonK-A., NamaziS., BarnardN., FujibayashiM., BhanotG., GanesanS., IyatomiH., OgawaK. & ShinbrotT. (2012). Automated reconstruction algorithm for identification of 3D architectures of cribriform ductal carcinoma in situ. PLoS One7, e44011.
47.
MageeD., SongY., GilbertS., RobertsN., WijayathungaN., WilcoxR., BulpittA. & TreanorD. (2015). Histopathology in 3D: From three-dimensional reconstruction to multi-stain and multi-modal analysis. Journal of Pathology Informatics6, 6.
48.
RobertsN., MageeD., SongY., BrabazonK., ShiresM., CrellinD., OrsiN.M., QuirkeR., QuirkeP. & TreanorD. (2012). Toward routine use of 3D histopathology as a research tool. American Journal of Pathology180, 1835–1842.
49.
BoothM.E., TreanorD., RobertsN., MageeD.R., SpeirsV. & HanbyA.M. (2015). Three-dimensional reconstruction of ductal carcinoma in situ with virtual slides. Histopathology66, 966–973.
50.
BrownP.J., TohE-W., SmithK.J.E., JonesP., TreanorD., MageeD., BurkeD. & QuirkeP. (2015). New insights into the lymphovascular microanatomy of the colon and the risk of metastases in pT1 colorectal cancer obtained with quantitative methods and three-dimensional digital reconstruction. Histopathology67, 167–175.
51.
HalldorssonS., LucumiE., Gómez-SjöbergR. & FlemingR.M.T. (2015). Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices. Biosensors & Bioelectronics63, 218–231.
52.
EcclesS.A., AboagyeE.O., AliS., AndersonA.S., ArmesJ., BerditchevskiF., BlaydesJ.P., BrennanK., BrownN.J., BryantH.E., BundredN.J., BurchellJ.M., CampbellA.M., CarrollJ.S., ClarkeR.B., ColesC.E., CookG.J., CoxA., CurtinN.J., DekkerL.V., Silva IdosS., DuffyS.W., EastonD.F., EcclesD.M., EdwardsD.R., EdwardsJ., EvansD., FenlonD.F., FlanaganJ.M., FosterC., GallagherW.M., Garcia-ClosasM., GeeJ.M., GescherA.J., GohV., GrovesA.M., HarveyA.J., HarvieM., HennessyB.T., HiscoxS. (2013). Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Research15, R92.
