Transcriptional Repression by FoxM1 Suppresses Tumor Differentiation and Promotes Metastasis of Breast Cancer
- 18 May 2022
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 82 (13), 2458-2471
- https://doi.org/10.1158/0008-5472.can-22-0410
Abstract
The transcription factor Forkhead box M1 (FoxM1) is overexpressed in breast cancers and correlates with poor prognosis. Mechanistically, FoxM1 associates with CBP to activate transcription and with Rb to repress transcription. Although the activating function of FoxM1 in breast cancer has been well documented, the significance of its repressive activity is poorly understood. Using CRISPR–Cas9 engineering, we generated a mouse model that expresses FoxM1-harboring point mutations that block binding to Rb while retaining its ability to bind CBP. Unlike FoxM1-null mice, mice harboring Rb-binding mutant FoxM1 did not exhibit significant developmental defects. The mutant mouse line developed PyMT-driven mammary tumors that were deficient in lung metastasis, which was tumor cell-intrinsic. Single-cell RNA-seq of the tumors revealed a deficiency in prometastatic tumor cells and an expansion of differentiated alveolar type tumor cells, and further investigation identified that loss of the FoxM1/Rb interaction caused enhancement of the mammary alveolar differentiation program. The FoxM1 mutant tumors also showed increased Pten expression, and FoxM1/Rb was found to activate Akt signaling by repressing Pten. In human breast cancers, expression of FoxM1 negatively correlated with Pten mRNA. Furthermore, the lack of tumor-infiltrating cells in FoxM1 mutant tumors appeared related to decreases in pro-metastatic tumor cells that express factors required for infiltration. These observations demonstrate that the FoxM1/Rb-regulated transcriptome is critical for the plasticity of breast cancer cells that drive metastasis, identifying a prometastatic role of Rb when bound to FoxM1. This work provides new insights into how the interaction between FoxM1 and Rb facilitates the evolution of metastatic breast cancer cells by altering the transcriptome.Other Versions
Funding Information
- NCI (5 RO1 CA243247, I01 BX000131)
- Department of Veterans Affair
- Biomedical Laboratory Research Development Service
- NIH (R35GM131707)
This publication has 52 references indexed in Scilit:
- GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expressionNature, 2013
- FoxM1 Regulates Mammary Luminal Cell FateCell Reports, 2012
- A Systematic Screen for CDK4/6 Substrates Links FOXM1 Phosphorylation to Senescence Suppression in Cancer CellsCancer Cell, 2011
- FoxM1 Promotes β-Catenin Nuclear Localization and Controls Wnt Target-Gene Expression and Glioma TumorigenesisCancer Cell, 2011
- FoxM1 Mediates Resistance to Herceptin and PaclitaxelCancer Research, 2010
- A Conserved Phosphorylation Site within the Forkhead Domain of FoxM1B Is Required for Its Activation by Cyclin-CDK1Online Journal of Public Health Informatics, 2009
- CD4+ T Cells Regulate Pulmonary Metastasis of Mammary Carcinomas by Enhancing Protumor Properties of MacrophagesCancer Cell, 2009
- The Retinoblastoma Protein Tumor Suppressor Is Important for Appropriate Osteoblast Differentiation and Bone DevelopmentMolecular Cancer Research, 2008
- Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progressionNature, 2008
- GATA-3 Links Tumor Differentiation and Dissemination in a Luminal Breast Cancer ModelCancer Cell, 2008