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| Status |
Public on Mar 03, 2023 |
| Title |
Coordinated Activation of c-Src and FOXM1 Drives Tumor Cell Proliferation and Breast Cancer Progression |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcome, yet the underlying mechanisms are incompletely understood. Here, we show that deleting c-Src abrogates the activity of Forkhead Box M1 (FOXM1), a master transcriptional regulator of the cell cycle, in a genetically engineered model mimicking the Luminal B molecular subtype of breast cancer. By phosphorylating it on two tyrosine residues, c-Src stimulates the nuclear localization of FOXM1 and the expression of its target genes, including key regulators of G2-M cell cycle progression as well as c-Src itself. This positive feedback loop drives proliferation in genetically engineered and patient-derived models of Luminal B-like breast cancer. Targeting this mechanism, including through novel compounds that destabilize the FOXM1 protein, induces G2-M cell cycle arrest and apoptosis, blocking tumor progression and impairing metastasis. We identify positive correlation of FOXM1 and c-Src expression in human breast cancer and show that the expression of FOXM1 target genes predicts poor outcome and associates with the Luminal B subtype, which responds poorly to approved therapies. These findings indicate that a regulatory network centered on c-Src and FOXM1 is a targetable vulnerability in aggressive luminal breast cancers.
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| Overall design |
Mammary epithelial organoids from a doxycycline-inducible transgenic model of breast cancer (MMTV-rtTA/TetO-PyVmT-IRES-CRE) were used to study the effects of c-Src (Src) deletion on early events in tumorigenesis. Transcriptomic analysis (RNA-Seq) was performed on organoid preparations from three independent groups of mice (n=5) per genotype (wild-type and conditional c-Src knockout), with and without doxycycline treatment to induce expression of the transforming oncogene (polyomavirus middle-T antigen) and Cre recombinase.
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| Contributor(s) |
Nandi I, Smith HW, Sanguin-Gendreau V, Ji L, Pacis A, Papavasiliou V, Zuo D, Nam S, Attala S, Kim SH, Lusson S, Kuasne H, Fortier A, Savage P, Martinez Ramirez C, Park M, Katzenellenbogen JA, Katzenellenbogen BS, Muller WJ |
| Citation(s) |
36795481 |
| Submission date |
Feb 08, 2023 |
| Last update date |
May 02, 2023 |
| Contact name |
Harvey Wilmore Smith |
| E-mail(s) |
harvey.smith2@mcgill.ca
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| Organization name |
McGill University
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| Department |
Goodman Cancer Research Centre
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| Street address |
Life Sciences Complex, Room 602, 1160 Pine Avenue West
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| City |
Montreal |
| State/province |
Quebec |
| ZIP/Postal code |
H3A 1A3 |
| Country |
Canada |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA932832 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE224876_FPKM_all_organoid_samples.xls.gz |
2.2 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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