Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis
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Curated by eLife
Evaluation Summary:
The long non-coding RNA HOTAIR has been widely reported to be overexpressed in many cancers, including breast cancer, and is strongly associated with disease progression and poor patient outcomes. A valuable new mouse model was developed for studying the functional effects of overexpressing HOTAIR and the mechanism of action of HOTAIR and used to demonstrate overexpression of HOTAIR promoted breast cancer metastasis to the lung. The mouse model and the conclusions will be of interest to researchers interested in improving treatment for breast cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
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Abstract
HOTAIR is a 2.2-kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We show that sustained high levels of HOTAIR over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of HOTAIR overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted EMT. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program. Targeting HOTAIR lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.
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Evaluation Summary:
The long non-coding RNA HOTAIR has been widely reported to be overexpressed in many cancers, including breast cancer, and is strongly associated with disease progression and poor patient outcomes. A valuable new mouse model was developed for studying the functional effects of overexpressing HOTAIR and the mechanism of action of HOTAIR and used to demonstrate overexpression of HOTAIR promoted breast cancer metastasis to the lung. The mouse model and the conclusions will be of interest to researchers interested in improving treatment for breast cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this manuscript, the authors have characterized the action of HOTAIR in enhancing tumor metastasis using a doxycycline-inducible transgenic mouse model. The authors have shown that the breast tumor cells are addicted to HOTAIR expression. In addition, the authors have shown that HOTAIR overexpression modulates both the cellular transcriptome and chromatin accessibility landscape for multiple metastasis-associated genes, and promoted epithelial to mesenchymal transition. The authors present numerous intriguing observations, and the findings are well supported by the data, Overall, this is an excellent manuscript that uncovers many interesting new aspects of HOTAIR in breast tumors. The strengths of this manuscript include the use of appropriate in vivo mouse cancer models, detailed analyses, and high …
Reviewer #1 (Public Review):
In this manuscript, the authors have characterized the action of HOTAIR in enhancing tumor metastasis using a doxycycline-inducible transgenic mouse model. The authors have shown that the breast tumor cells are addicted to HOTAIR expression. In addition, the authors have shown that HOTAIR overexpression modulates both the cellular transcriptome and chromatin accessibility landscape for multiple metastasis-associated genes, and promoted epithelial to mesenchymal transition. The authors present numerous intriguing observations, and the findings are well supported by the data, Overall, this is an excellent manuscript that uncovers many interesting new aspects of HOTAIR in breast tumors. The strengths of this manuscript include the use of appropriate in vivo mouse cancer models, detailed analyses, and high translational potential.
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Reviewer #2 (Public Review):
The manuscript is well written, and clearly presented. The results are of general interest and present an attractive perspective on manipulating HOTAIR in breast cancer patients that could help to design a novel drug for treatments. However, some important description and characterization are needed to complete the full interpretation of the data, especially concerning the absence of epigenetic memory followed by the interruption of HOTAIR expression. As they stand, loss of epigenetic memory has to be further demonstrated, especially for non-chromatin epigenetic status. More detailed experiments are required to make firm conclusions on this aspect of the study. In addition, despite a great and fully documented phenotypical description, using a large variety of approaches, the analyses of human HOTAIR …
Reviewer #2 (Public Review):
The manuscript is well written, and clearly presented. The results are of general interest and present an attractive perspective on manipulating HOTAIR in breast cancer patients that could help to design a novel drug for treatments. However, some important description and characterization are needed to complete the full interpretation of the data, especially concerning the absence of epigenetic memory followed by the interruption of HOTAIR expression. As they stand, loss of epigenetic memory has to be further demonstrated, especially for non-chromatin epigenetic status. More detailed experiments are required to make firm conclusions on this aspect of the study. In addition, despite a great and fully documented phenotypical description, using a large variety of approaches, the analyses of human HOTAIR expression in ES cells and/or cancer cells plus mice primary tumors would have benefited from in situ RNA localization experiments both at subcellular compartments and chromatin loci level.
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Reviewer #3 (Public Review):
A new mouse model was developed for studying a cancer-associated factor named HOTAIR. Increased levels of HOTAIR promoted the spread ("metastasis") of breast cancer to the lung. The high levels of HOTAIR consequently activated many specific genes that are known to play important roles in the ability of cancer cells to spread. As breast cancer cells depended on HOTAIR in order to spread, targeting HOTAIR may be a therapeutic target for treating breast cancer in patients in general and preventing cancer cells from metastasizing to the other parts of the body.
This is an exciting and important study. The iHOT-PyMT mouse is novel and for the first time provides a valuable model for studying the in vivo function and mechanism of action of one of the most well-known and important lncRNAs HOTAIR. The study …
Reviewer #3 (Public Review):
A new mouse model was developed for studying a cancer-associated factor named HOTAIR. Increased levels of HOTAIR promoted the spread ("metastasis") of breast cancer to the lung. The high levels of HOTAIR consequently activated many specific genes that are known to play important roles in the ability of cancer cells to spread. As breast cancer cells depended on HOTAIR in order to spread, targeting HOTAIR may be a therapeutic target for treating breast cancer in patients in general and preventing cancer cells from metastasizing to the other parts of the body.
This is an exciting and important study. The iHOT-PyMT mouse is novel and for the first time provides a valuable model for studying the in vivo function and mechanism of action of one of the most well-known and important lncRNAs HOTAIR. The study represents an important contribution to basic, clinical and translational research. The experiments are rigorous and appropriate controls were used throughout the study, providing confidence in the large amount of data presented in the manuscript. The results support the conclusions made by the authors.
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