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Review
. 2004 Oct;9(4):297-310.
doi: 10.1007/s10911-004-1402-z.

Use of three-dimensional basement membrane cultures to model oncogene-induced changes in mammary epithelial morphogenesis

Kenna R Mills Shaw  1 , Carolyn N Wrobel, Joan S Brugge
Affiliations
Review

Use of three-dimensional basement membrane cultures to model oncogene-induced changes in mammary epithelial morphogenesis

Kenna R Mills Shaw et al. J Mammary Gland Biol Neoplasia. 2004 Oct.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Modeling epithelial morphogenesis in basement membrane gels. Epithelial cells, such as the MCF-10A human mammary line, follow a reproducible morphogenetic program when seeded within an exogenous matrix. Single cells proliferate to form clonal cyst-like structures, which develop an axis of polarity and form hollow lumens, a process that involves death of the inner cells. Cartoon images of acini were modified from a figure in Ref. (12).
Fig. 2
Fig. 2
Distinct alterations in 3D morphogenesis result from hyperactivation of different RTKs. Phase and confocal immunofluorescence images of day 17 structures formed by parental MCF-10As or cells overexpressing ErbB2 (32), CSF-1R/CSF-1 (37), or c-Met/HGF (37) are shown. Structures were stained with DAPI (blue) and an antibody to the cleaved form of caspase-3 (green). The CSF-1R/CSF-1 confocal image was reproduced from ref. (37).
Fig. 3
Fig. 3
Cooperation between proliferative and survival signals results in filling of acinar lumen. Confocal sections of DAPI-stained day 20 structures formed by parental MCF-10As or cells overexpressing cyclin D1 or cyclin D1/Bcl-2 are shown. Inset, staining of cyclin D1 acini with DAPI (blue) and an antibody to the cleaved form of caspase-3 (green) reveals elevated levels of luminal apoptosis in these structures (13). The MCF-10A and cyclin D1 panels were reproduced from ref. (13).
Fig. 4
Fig. 4
Multiple oncogenes can cooperate to elicit an invasive phenotype. Phase images of day 12 structures formed by MCF-10As overexpressing ErbB2 or ErbB2/TGFβ. These images were reproduced from Ref. (64).
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