title: FOXC2 regulates the G2/M transition of stem cell-rich breast cancer cells and sensitizes them to PLK1 inhibition.
abstract: Cancer cells with stem cell properties (CSCs) underpin the chemotherapy resistance and high therapeutic failure of triple-negative breast cancers (TNBCs). Even though CSCs are known to proliferate more slowly, they are sensitive to inhibitors of G2/M kinases such as polo-like kinase 1 (PLK1). Understanding the cell cycle regulatory mechanisms of CSCs will help target these cells more efficiently. Herein, we identify a novel role for the transcription factor FOXC2, which is mostly expressed in CSCs, in the regulation of cell cycle of CSC-enriched breast cancer cells. We demonstrate that FOXC2 expression is regulated in a cell cycle-dependent manner, with FOXC2 protein levels accumulating in G2, and rapidly decreasing during mitosis. Knockdown of FOXC2 in CSC-enriched TNBC cells delays mitotic entry without significantly affecting the overall proliferation rate of these cells. Moreover, PLK1 activity is important for FOXC2 protein stability, since PLK1 inhibition reduces FOXC2 protein levels. Indeed, FOXC2 expressing CSC-enriched TNBC cells are sensitive to PLK1 inhibition. Collectively, our findings demonstrate a novel role for FOXC2 as a regulator of the G2/M transition and elucidate the reason for the observed sensitivity of CSC-enriched breast cancer cells to PLK1 inhibitor.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Pietilä
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Geraldine V
authors.initials: GV
authors.lastname: Vijay
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Soundararajan
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Symmans
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sphyris
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.|Metastasis Research Centre, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.|Center for Stem Cells and Developmental Biology, The University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
mesh_terms: D001943:Breast Neoplasms / Q000503:physiopathology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C082078:mesenchyme fork head 1 protein