Nontransgenic models of breast cancer

Heppner, Gloria H.; Miller, Fred R.; Shekhar, PV Malathy

doi:10.1186/bcr77

Cited by 226 publications

(232 citation statements)

References 13 publications

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“…We tested this idea by growing multicellular structures from Michigan Cancer Foundation-7 (MCF-7) cells and then quantifying the extent of line formation and disorganization. The MCF-7 cell line was originally derived from a patient with invasive ductal carcinoma, represents an advanced stage of tumor progression (37,38), and has further compromised integrity of cell-cell adhesion (39,40). When grown, extracted, and deposited on collagen 1 like the MCF10AT acini, the MCF-7 spheroids more readily spread, as expected.…”

Section: Significancementioning

confidence: 90%

Rapid disorganization of mechanically interacting systems of mammary acini

Shi

Ghosh

Engelke

et al. 2013

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

138

177

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Cells and multicellular structures can mechanically align and concentrate fibers in their ECM environment and can sense and respond to mechanical cues by differentiating, branching, or disorganizing. Here we show that mammary acini with compromised structural integrity can interconnect by forming long collagen lines. These collagen lines then coordinate and accelerate transition to an invasive phenotype. Interacting acini begin to disorganize within 12.5 ± 4.7 h in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize more slowly (in 21.8 ± 4.1 h) and to a lesser extent (P < 0.0001). When the directed mechanical connections between acini were cut with a laser, the acini reverted to a slowly disorganizing phenotype. When acini were fully mechanically isolated from other acini and also from the bulk gel by box-cuts with a side length <900 μm, transition to an invasive phenotype was blocked in 20 of 20 experiments, regardless of waiting time. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix, and these directed mechanical interactions facilitate transition to an invasive phenotype.mechanobiology | cancer E pithelial cells are physically coupled to their neighbors and are also in contact with the ECM. The ECM confers mechanical integrity to tissues and provides chemical, anatomical, and mechanical signals to cells, influencing differentiation, development, and pathogenesis (1-11). The extent to which mechanical cues are generated and received by individual cells has been studied both experimentally and theoretically (12)(13)(14). Progress has also been made in understanding the signaling pathways that cells use to sense external mechanics. Cell-ECM interactions are mediated in part by transmembrane proteins typified by the integrins, which link the cell's internal actin cytoskeleton with extracellular collagen fibers (15). Cells use multiple approaches for integrating mechanical cues with biochemical cues provided by soluble factors; for example, there is extensive multilayered cross-talk between integrin and TGF-β signaling (16,17). It is now also clear that key developmental regulators, such as Notch, can be directly activated by mechanical force (18,19).Less is known about the interactions of organized multicellular structures with the ECM and how those interactions affect tissue architecture, composition, and stability, as well as the molecular pathways by which these effects are mediated. In certain situations, contractile multicellular structures are able to mechanically reorganize biopolymer networks over long distances and in a highly directional manner, generating what are variously referred to as fibers, tracts, cables, straps, or lines. Regions of highly directional collagen alignment and concentration have been seen in systems ranging from single cells and tumor explants to human clinical samples (6,8,10,(20)(21)(22). Vader et al. demonstrated that the formation of long collagen lines is ...

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Section: Significancementioning

confidence: 90%

Rapid disorganization of mechanically interacting systems of mammary acini

Shi

Ghosh

Engelke

et al. 2013

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

138

177

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“…Here, we have inhibited FAK activity or FAK expression in murine 4T1 breast carcinoma cells via transient FRNK or stable anti-FAK short hairpin RNA (shRNA) expression, respectively. 4T1 cells are derived from a spontaneously arising BALB/c mouse mammary tumor, are highly metastatic and are used as a late-stage model for human breast cancer (Aslakson and Miller, 1992;Heppner et al, 2000). Focal adhesion kinase shRNA expression resulted in the inhibition of 4T1 cell invasion in vitro and spontaneous 4T1 metastasis after orthotopic implantation.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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Expression of focal adhesion kinase (FAK) is elevated in malignant breast cancer, yet the role of intrinsic FAK activity in promoting tumor progression remains undefined. Here, we have inhibited FAK activity or expression in murine 4T1 breast carcinoma cells via dominantnegative focal adhesion kinase-related non-kinase (FRNK) or anti-FAK short hairpin RNA (shRNA) expression, respectively. Neither FRNK nor FAK shRNA (B80% reduced FAK levels) affected 4T1 proliferation in culture, whereas reduced FAK activity or expression blocked 4T1 cell invasion through Matrigel and resulted in 2-3-fold lower urokinase plasminogen activator (uPA) expression. Control 4T1 cells implanted into mammary fat pads of BALB/c mice exhibited spontaneous metastasis to the lungs, to the peritoneal cavity, and resulted in 90% lethality within 21 days. Whereas FAK shRNAexpressing 4T1 cells formed tumors in mice with low levels of apoptosis, when mammary-injected, these cells did not exhibit lung metastasis after 21 days and caused only 40% lethality up to 60 days. Transient re-expression of wildtype but not kinase-dead FAK in 4T1 FAK shRNA cells promoted uPA production and mammary to lung metastasis within 7 days. In fact, stable human uPA overexpression in 4T1 FAK shRNA cells promoted Matrigel invasion and lung metastasis equal to 4T1 controls. Conversely, treatment with plasminogen activator inhibitor-1 or neutralizing antibody to uPA blocked Matrigel invasion of 4T1 control cells. These studies provide the first direct proof that FAK catalytic activity can facilitate metastatic breast cancer progression by regulating uPA expression.

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“…Another cell line from a similar source that had similar properties was the MCF-10A line established by Fred Miller and colleagues (Soule et al 1990). They too established a cancer progression continuum from the cell line but with the use of c-Ha-ras (Heppner et al 2000).…”

Section: Established Cell Linesmentioning

confidence: 99%