# Repression function of FoxM1 in metastasis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $358,456

## Abstract

Abstract/Summary
Metastasis is often the main cause of fatality from cancer. Despite significant progresses on the steps involved
in metastasis of tumor cells from a primary site to distal organs, our understanding of the molecular details of
how tumor cells evolve and acquire the ability to metastasize is sketchy. Some progress has been made on the
metastatic cells. For example, recent studies in breast cancer characterized cluster of disseminating tumor cells
expressing basal epithelial markers. Other studies indicated involvement of the cancer stem-like cells in
metastasis. This proposal focuses on the fork-head box transcription factor FoxM1 that is over-expressed in
aggressive types of breast cancer. The proposal is based on our new findings, which surprisingly indicate that
FoxM1’s interaction with the retinoblastoma (Rb) family proteins is important for tumor metastasis. The central
hypothesis in this proposal is that, the gene-repression function of FoxM1, involving the retinoblastoma family
proteins, plays critical roles in the progression of metastatic breast cancer.
FoxM1 stimulates proliferation/pro-cancer genes and represses differentiation genes. We were able to
genetically dissect the repressor function from the activation function. Phosphorylation of FoxM1 by Plk1
converts a transcriptional repressor form of FoxM1 to an activator form. In the absence of Plk1-phosphorylation,
FoxM1 binds to Rb to function as a repressor. Plk1 phosphorylated-FoxM1 does not bind Rb, instead it binds to
the co-activator CBP. Consistent with that, a Plk1-sites phospho-mimetic mutant of FoxM1 activates
transcription, but fails to bind Rb and fails to repress the differentiation gene GATA3. We have generated a
knock-in mouse strain that expresses the repression-deficient mutant of FoxM1 (FoxM1DD). Unlike FoxM1-/-
mice, there is no overt developmental defect, except that the females exhibit deficiencies in lactation.
Interestingly, the FoxM1DD/DD mice support MMTV-PyMT-driven development of mammary tumors as
efficiently as FoxM1 +/DD, but the tumors in FoxM1 DD/DD mice are severely deficient in metastasis. We will
use this mouse model and a model for basal-like tumors to investigate how gene repression function of FoxM1
drives metastasis. The aims are:
1. Investigate whether metastasis deficiency in the FoxM1 DD/DD mice is related to deficiencies in the
 development of the basal epithelial metastatic cells and cancer stem-like cells.
2. Investigate the FoxM1 repressed genes that regulate evolution of metastatic cells.
3. Investigate whether the repression function of FoxM1 is required for metastasis of basal-like tumors.

## Key facts

- **NIH application ID:** 10460966
- **Project number:** 5R01CA243247-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Pradip Raychaudhuri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $358,456
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460966

## Citation

> US National Institutes of Health, RePORTER application 10460966, Repression function of FoxM1 in metastasis (5R01CA243247-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10460966. Licensed CC0.

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