The development of a functionally relevant cell culture model of progressive human breast cancer

Weaver, Valerie M.; Howlett, Anthony R.; Langton-Webster, Beatrice; Petersen, Ole W.; Bissell, Mina J.

doi:10.1006/scbi.1995.0021

Cited by 119 publications

(96 citation statements)

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“…While S1 cells form well-organized acinar structures exhibiting apicobasal polarity and stable adherens junctions, T4-2 cells form highly disorganized and discohesive structures. In accordance with the hypothesis that 3D culture better recapitulates in vivo behavior, only the latter cell type is tumorigenic when transplanted in nude mice (20).…”

Section: D Cultures Reveal Transformation-induced Changes In Mammarysupporting

confidence: 56%

Use of Three-Dimensional Basement Membrane Cultures to Model Oncogene-Induced Changes in Mammary Epithelial Morphogenesis

Shaw

Wrobel

Brugge

2004

J Mammary Gland Biol Neoplasia

137

117

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The development of breast carcinomas involves a complex set of phenotypic alterations in breast epithelial cells and the surrounding microenvironment. While traditional transformation assays provide models for investigating certain aspects of the cellular processes associated with tumor initiation and progression, they do not model alterations in tissue architecture that are critically involved in tumor development. In this review, we provide examples of how three-dimensional (3D) cell culture models can be utilized to dissect the pathways involved in the development of mammary epithelial structures and to elucidate the mechanisms responsible for oncogene-induced phenotypic alterations in epithelial behavior and architecture. Many normal mammary epithelial cell lines undergo a stereotypic morphogenetic process when grown in the presence of exogenous matrix proteins. This 3D morphogenesis culminates in the formation of well-organized, polarized spheroids, and/or tubules that are highly reminiscent of normal glandular architecture. In contrast, transformed cell lines isolated from mammary tumors exhibit significant deviations from normal epithelial behavior in 3D culture. We describe the use of 3D models as a method for both reconstructing and deconstructing the cell biological and biochemical events involved in mammary neoplasia.Keywords mammary epithelial cells; breast cancer; morphogenesis; 3D cell culture; oncogenesis Abbreviations used3D; three-dimensional; BARD-1, BRCA-1 associated ring domain; CDK, cyclin-dependent kinase; CGH, comparative genomic hybridization; CSF-1, colony-stimulating factor; CSF-1R, colonystimulating factor receptor; DCIS, ductal carcinoma in situ; E7, human papilloma virus 16 E7 protein; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EHS, Engelbreth-Holm-Swarm; EMT, epithelial-to-mesenchymal transition; ER, estrogen receptor; GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IL-1, interleukin-1; MAPK, mitogen-activated protein kinase; MEC, mammary epithelial cell; MMP, matrix metalloproteinase; MMTV, mouse mammary tumor virus; PI3K, phosphotidylinositol-3 kinase; PR, progesterone receptor; Rb, retinoblastoma protein; TGFβ, transforming growth factor beta; VEGF, vascular endothelial growth factor 2 To whom correspondence should be addressed at Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115; e-mail: joan brugge@hms.harvard.edu.. 3 These authors contributed equally to this review. NIH Public AccessAuthor Manuscript J Mammary Gland Biol Neoplasia. Author manuscript; available in PMC 2006 July 17. FROM SOFT AGAR TO BASEMENT MEMBRANE GELS: MODELING MAMMARY TUMORIGENESIS IN VITROThe mammary gland is a complex organ, comprised of multiple cell types and surrounded by a proteinaceous extracellular matrix (ECM). Mammary epithelial cells (MECs) represent the fundamental functional unit of the gland and comprise a polariz...

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Section: D Cultures Reveal Transformation-induced Changes In Mammarysupporting

confidence: 56%

Use of Three-Dimensional Basement Membrane Cultures to Model Oncogene-Induced Changes in Mammary Epithelial Morphogenesis

Shaw

Wrobel

Brugge

2004

J Mammary Gland Biol Neoplasia

137

117

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“…HMT-3522 S1, HMT-3522 T4-2 mammary epithelial cells (76)(77)(78), MCF-10A, Hs578T, MCF-7, MDA-MB-231, and SKBR-3 (American Type Culture Collection) were cultured (79) (SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Veiseh

Kwon

Borowsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA −/low vs. HA high ) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA high subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA −/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.tumor cell heterogeneity | hyaluronan binding | heterogeneity index B reast tumors display substantial heterogeneity driven by genetic and epigenetic mechanisms (1-3). These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3-12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3, 13-15), the phenotypes manifested from this diversity are context-dependent. Therefore, phenotypic markers provide additional powerful tools for biological information required to design diagnostics and therapeutics. Glycomic approaches have enormous potential for revealing tumor cell phenotypic heterogeneity because glycans are themselves highly heterogeneous and their complexity reflects the nutritional, microenvironmental, and genetic dynamics of the tumors (16-18).We used hyaluronan (HA) as a model carbohydrate ligand for probing heterogeneity in glycosaminoglycan-BCa cell receptor interactions. We reasoned this approach...

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“…Moreover, providing a microenvironment with adequate adhesion and proliferation has been reported to allow a more accurate investigation of cellular homeostasis, differentiation and migration (Kim, 2005;Kim et al, 2004). The use of collagen gels and more complex multi-component systems such as Matrigel has become increasingly popular, as they provide the cells with a matrix which more accurately represents the extra cellular matrix (ECM) (Petersen et al, 1992;Prestwich, 2008;Weaver et al, 1995). The impact of such matrices on the cell phenotype and metabolism has been already documented in the literature.…”

Section: Introductionmentioning

confidence: 99%

Cell viability assessment using the Alamar blue assay: A comparison of 2D and 3D cell culture models

Bonnier¹,

Keating²,

Wróbel

et al. 2015

Toxicology in Vitro

209

164

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The development of a functionally relevant cell culture model of progressive human breast cancer

Cited by 119 publications

References 0 publications

Use of Three-Dimensional Basement Membrane Cultures to Model Oncogene-Induced Changes in Mammary Epithelial Morphogenesis

Use of Three-Dimensional Basement Membrane Cultures to Model Oncogene-Induced Changes in Mammary Epithelial Morphogenesis

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Cell viability assessment using the Alamar blue assay: A comparison of 2D and 3D cell culture models

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