Abstract
BackgroundThe basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation. There is evidence to indicate that Twist expression plays a role in breast tumor formation and metastasis, but the role of Twist in dysregulating pathways that drive the metastatic cascade is unclear. Moreover, many of the genes and pathways dysregulated by Twist in cell lines and mouse models have not been validated against data obtained from larger, independant datasets of breast cancer patients.MethodsWe over-expressed the human Twist gene in non-metastatic MCF-7 breast cancer cells to generate the estrogen-independent metastatic breast cancer cell line MCF-7/Twist. These cells were inoculated in the mammary fat pad of female severe compromised immunodeficient mice, which subsequently formed xenograft tumors that metastasized to the lungs. Microarray data was collected from both in vitro (MCF-7 and MCF-7/Twist cell lines) and in vivo (primary tumors and lung metastases) models of Twist expression. Our data was compared to several gene datasets of various subtypes, classes, and grades of human breast cancers.ResultsOur data establishes a Twist over-expressing mouse model of breast cancer, which metastasizes to the lung and replicates some of the ontogeny of human breast cancer progression. Gene profiling data, following Twist expression, exhibited novel metastasis driver genes as well as cellular maintenance genes that were synonymous with the metastatic process. We demonstrated that the genes and pathways altered in the transgenic cell line and metastatic animal models parallel many of the dysregulated gene pathways observed in human breast cancers.ConclusionsAnalogous gene expression patterns were observed in both in vitro and in vivo Twist preclinical models of breast cancer metastasis and breast cancer patient datasets supporting the functional role of Twist in promoting breast cancer metastasis. The data suggests that genetic dysregulation of Twist at the cellular level drives alterations in gene pathways in the Twist metastatic mouse model which are comparable to changes seen in human breast cancers. Lastly, we have identified novel genes and pathways that could be further investigated as targets for drugs to treat metastatic breast cancer.
Highlights
The basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation
We demonstrate that the genes and pathways altered in our Twist over expressing cell line and metastatic xenograft mouse model recapitulate some of the observations seen in human breast tumors
Experimental study design and bioinformatics analysis To study genomic pathways that are disrupted by Twist expression in breast cancer, we designed an experimental plan that encompasses cell culture, a mouse xenograft model, and human breast cancer samples (Fig. 1)
Summary
The basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation. Many of the genes and pathways dysregulated by Twist in cell lines and mouse models have not been validated against data obtained from larger, independant datasets of breast cancer patients. If genetic changes that contribute to breast cancer progression can be catalogued using cell line and xenograft-based models, it may be possible to derive gene signatures that, at least partly, replicate the progression of breast cancer in humans. This could be accomplished in cell lines that ordinarily do not express these genes. We demonstrate that the genes and pathways altered in our Twist over expressing cell line and metastatic xenograft mouse model recapitulate some of the observations seen in human breast tumors. Our data establishes a new mouse model of metastatic breast cancer that can be used to test the efficacy of therapies for breast cancer treatment
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