The morphologies of breast cancer cell lines in three‐dimensional assays correlate with their profiles of gene expression

Kenny, Paraic A.; Lee, Genee Y.; Myers, Connie A.; Neve, Richard M.; Semeiks, Jeremy R.; Spellman, Paul T.; Lorenz, Katrin; Lee, Eva H.; Barcellos‐Hoff, Mary Helen; Petersen, Ole W.; Gray, Joe W.; Bissell, Mina J.

doi:10.1016/j.molonc.2007.02.004

Cited by 877 publications

(969 citation statements)

References 58 publications

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“…14 Morphology on BME also has been used to define specific stages of breast cancer progression based on behaviors, such as acinar structure formation, cell polarization, colony formation, proliferation, and invasion in 3D culture. [38][39][40] The implementation of 3D coculture models is currently in its infancy but shows great promise for the future. Threedimensional coculture models incorporate additional cell types with cancer cells within a physiological environment to better recapitulate the cancer cell niche.…”

Section: Cell Morphology Growth and Coculturementioning

confidence: 99%

Multiple uses of basement membrane‐like matrix (BME/Matrigel) in vitro and in vivo with cancer cells

Benton

Kleinman

George

et al. 2011

Intl Journal of Cancer

184

134

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Significant advances in our understanding of cancer cell behavior, growth, and metastasis have been facilitated by studies using a basement membrane-like extracellular matrix extract, also known as Matrigel. The basement membrane is a thin extracellular matrix that is found in normal tissues and contacts epithelial and endothelial cells, smooth muscle, fat, Schwann cells, etc. It is composed of mainly laminin-111, collagen IV, heparan sulfate proteoglycan, entactin/nidogen, and various growth factors (fibroblast growth factor, transforming growth factor beta, epidermal growth factor, etc.). Most tumors of epithelial origin produce significant amounts of basement membrane matrix and interact with it particularly during metastasis. Cancer cells metastasize via degradation of the vessel basement membrane matrix to extravasate into the blood stream and colonize distant sites. This review will focus on the interaction of cancer cells and cancer stem cells with the basement membrane-like matrix and the various uses of this interaction to accelerate tumor growth in vivo and to develop in vitro assays for invasion, morphology, and dormancy. Such assays and methods have advanced our understanding of the process of cancer progression, the genes and pathways that are involved, the potential of various therapeutic agents, the effects of neighboring cells, and the role of stem cells.

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Section: Cell Morphology Growth and Coculturementioning

confidence: 99%

Multiple uses of basement membrane‐like matrix (BME/Matrigel) in vitro and in vivo with cancer cells

Benton

Kleinman

George

et al. 2011

Intl Journal of Cancer

184

134

View full text Add to dashboard Cite

show abstract

“…We set out to explore ECM‐mediated regulation of expression of the lncRNA HOTAIR in Claudin‐low breast cancer cells using lrECM 3D culture (Kenny et al ., 2007b; Prat et al ., 2010). We chose Claudin‐low MDA‐MB‐231 and Hs578T cells because of their invasive and metastatic competence (Neve et al ., 2006; Prat et al ., 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Stellate morphology of both cell lines featured irregular cell clusters and projections formed by chains of cells that intersected occasionally as described elsewhere (Fig. 1C, indicated by red arrowheads) (Kenny et al ., 2007b). …”

Section: Resultsmentioning

confidence: 99%

“…1C; Kenny et al ., 2007b; Li et al ., 2016). A correlation between induction of HOTAIR and invasive growth prompted us to examine the role of HOTAIR in invasive growth in lrECM 3D culture.…”

Section: Resultsmentioning

confidence: 99%

“…These findings likely reflect the complexity in composition of ECM and the signaling pathways in response to ECM. Interference of other integrin receptors and kinases individually and in combination, such as integrin α6 (major receptors for laminin), is still needed to determine the role of each individual ECM and its responsive cellular signaling molecules in the activation of HOTAIR expression (Kenny et al ., 2007b; Lee et al ., 2007; Lu et al ., 2012; Weaver et al ., 1997; Ziober et al ., 1999). More importantly, our results indicate that HOTAIR expression is required for invasive growth of Claudin‐low breast cancer cells, particularly cell viability (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

Zhuang

et al. 2017

Molecular Oncology

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Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin‐low MDA‐MB‐231 and Hs578T cells in two‐dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin‐rich extracellular matrix‐based three‐dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR‐specific siRNA. Induction of HOTAIR in lrECM 3D culture resulted from the activation of a novel isoform of HOTAIR (HOTAIR‐N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR‐N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lrECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR‐N promoter in Claudin‐low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin‐low breast cancer cells in lrECM 3D culture.

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The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings

et al. 2021

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Dormant, disseminated tumor cells (DTCs) are thought to be the source of breast cancer metastases several years or even decades after initial treatment. To date, a selective therapy that leads to their elimination has not been discovered. While dormant DTCs resist chemotherapy, evidence suggests that this resistance is driven not by their lack of proliferation, but by their engagement of the surrounding microenvironment, via integrin‐β1‐mediated interactions. Because integrin‐β1‐targeted agents have not been translated readily to the clinic, signaling nodes downstream of integrin‐β1 could serve as attractive therapeutic targets in order to sensitize dormant DTCs to therapy. By probing a number of kinases downstream of integrin‐β1, we determined that PI3K inhibition with either a tool compounds or a compound (PF‐05212384; aka Gedatolisib) in clinical trials robustly sensitizes quiescent breast tumor cells seeded in organotypic bone marrow cultures to chemotherapy. These results motivated the preclinical study of whether Gedatolisib—with or without genotoxic therapy—would reduce DTC burden and prevent metastases. Despite promising results in organotypic culture, Gedatolisib failed to reduce DTC burden or delay, reduce or prevent metastasis in murine models of either triple‐negative or estrogen receptor‐positive breast cancer dissemination and metastasis. This result held true whether analyzing Gedatolisib on its own (vs. vehicle‐treated animals) or in combination with dose‐dense doxorubicin and cyclophosphamide (vs. animals treated only with dose‐dense chemotherapies). These data suggest that PI3K is not the node downstream of integrin‐β1 that confers chemotherapeutic resistance to DTCs. More broadly, they cast doubt on the strategy to target PI3K in order to eliminate DTCs and prevent breast cancer metastasis.

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The morphologies of breast cancer cell lines in three‐dimensional assays correlate with their profiles of gene expression

Cited by 877 publications

References 58 publications

Multiple uses of basement membrane‐like matrix (BME/Matrigel) in vitro and in vivo with cancer cells

Multiple uses of basement membrane‐like matrix (BME/Matrigel) in vitro and in vivo with cancer cells

Induction of a novel isoform of the lncRNA HOTAIR in Claudin‐low breast cancer cells attached to extracellular matrix

The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings

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