Review Article

Gene Expression Analysis of In Vitro Cocultures to Study Interactions between Breast Epithelium and Stroma

Table 2

Whole genome microarray studies to investigate breast cancer tumor microenvironment in vitro.

Authors (citation)Cancer cell lines usedStromal cell lines usedType of cocultureSpecial separation techniquesLinked to human in vivo dataMajor findings

Rozenchan et al. (2009) [37]MCF10A, MDA-MB-231Primary CAFs and NAFsTranswellNoNoEpithelial cell lines upregulate different pathways when cocultured with the two types of fibroblasts. MDA-MB-231-CAF cocultures (CAFs) upregulate β-catenin/TCF pathway genes; MDA-MB-231-NAF cocultures downregulate glycolipid and fatty acid biosynthesis. MCF10A-CAF cocultures upregulate stress response genes, while MCF10A-NAF cocultures downregulate growth control and adhesion genes.

Santos et al. (2011) [38]MDA-MB-231, MDA-MB-435, MCF7Primary fibroblasts from positive and negative LNTranswellNoNoGene expression changes induced by coculture with fibroblasts from positive and negative nodes are distinct and intrinsic to each tumor subtype.

Camp et al. (2010) [35]MCF7, T47D, ZR75, Sum102, Sum149, HCC1537Immortalized reduction mammary fibroblastsDirect physical contact and transwellYesComputational deconvolutionThe response to fibroblast coculture differs between basal-like and luminal cancer cell lines. The genes that distinguish basal-like versus luminal cultures also distinguishes human tumors. Basal-likes upregulate interleukins and chemokines (IL-6, IL-8, CXCL1, CXCL3, TGF-β) and TWIST and SOD1. Luminal cells increase stress response genes.

Buess et al. (2009) [39]Hs578T, BT549, MDA-MB-436, MDA-MB-231, HMEC, SKBR-3, MCF7, T47D, HMECsStromal fibroblasts: human dermal fibroblasts, embryonic lung fibroblasts, and breasts fibroblastsDirect physical contact & transwellYesComputational deconvolutionInteraction between some breast cancer cells and stromal fibroblasts induced interferon response. The presence of this response is associated with higher risk of tumor progression.

Buess et al. (2009) [40]HMECs, MCF7, T47D, MDA-MB-231, SKBR-3, Hs578T, BT549HuVECs and human dermal microvascular endothelial cellsDirect physical contact & transwellYesComputational deconvolutionInduction of an “M-phase cell cycle genes” in breast cancer cell lines but not in normal epithelium. Tumors with this gene signature have increased metastasis and worse overall survival. Endothelial cells induce proliferation in CD44+/CD24− cancer cells.

Liu et al. (2011) [41]Sum159, Sum149, MCF7Human bone marrow-derived mesenchymal cellsDirect physical contact and transwellNoNoMSCs regulate cancer cell behavior through their effects on cancer stem cells. Networks of cytokines (IL-6, IL-8, CXCL1, CXCL5, and CXCL6 are associated with migration of cancer cells).

Wadlow et al. (2009) [42]Many commercially available cancer cell linesMany commercially available normal skin and lung fibroblastsDirect physical contactNoNoCancer cell proliferation is modulated both by the cancer cell and the fibroblasts. Two functionally distinct pathways associated with altered proliferation were identified, one of which showed features of activated mesenchyme.