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Bollu LR, Shepherd J, Zhao D, et al. Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1. NPJ Breast Cancer. 2020;6:2doi: 10.1038/s41523-019-0143-5.
Bollu, L. R., Shepherd, J., Zhao, D., Ma, Y., Tahaney, W., Speers, C., Mazumdar, A., Mills, G. B., & Brown, P. H. (2020). Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1. NPJ breast cancer, 62. https://doi.org/10.1038/s41523-019-0143-5
Bollu, Lakshmi Reddy, et al. "Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1." NPJ breast cancer vol. 6 (2020): 2. doi: https://doi.org/10.1038/s41523-019-0143-5
Bollu LR, Shepherd J, Zhao D, Ma Y, Tahaney W, Speers C, Mazumdar A, Mills GB, Brown PH. Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1. NPJ Breast Cancer. 2020 Jan 03;6:2. doi: 10.1038/s41523-019-0143-5. eCollection 2020. PMID: 31909186; PMCID: PMC6941974.
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NPJ Breast Cancer. 2020 Jan 03;6:2. doi: 10.1038/s41523-019-0143-5. eCollection 2020.

Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1.

NPJ breast cancer

Lakshmi Reddy Bollu, Jonathan Shepherd, Dekuang Zhao, Yanxia Ma, William Tahaney, Corey Speers, Abhijit Mazumdar, Gordon B Mills, Powel H Brown

Affiliations

  1. 1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas USA.
  2. 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas USA.
  3. 3Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan USA.
  4. 4Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas USA.
  5. 5Present Address: Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, 2720 Southwest Moody Avenue, Knight Cancer Research Building, Level 2, Portland, Oregon 97201 USA.

PMID: 31909186 PMCID: PMC6941974 DOI: 10.1038/s41523-019-0143-5

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and is associated with a poor prognosis due to frequent distant metastasis and lack of effective targeted therapies. Previously, we identified maternal embryonic leucine zipper kinase (MELK) to be highly expressed in TNBCs as compared with ER-positive breast cancers. Here we determined the molecular mechanism by which MELK is overexpressed in TNBCs. Analysis of publicly available data sets revealed that MELK mRNA is elevated in p53-mutant breast cancers. Consistent with this observation, MELK protein levels are higher in p53-mutant vs. p53 wild-type breast cancer cells. Furthermore, inactivation of wild-type p53, by loss or mutation of the p53 gene, increases MELK expression, whereas overexpression of wild-type p53 in p53-null cells reduces MELK promoter activity and MELK expression. We further analyzed MELK expression in breast cancer data sets and compared that with known wild-type p53 target genes. This analysis revealed that MELK expression strongly correlates with genes known to be suppressed by wild-type p53. Promoter deletion studies identified a p53-responsive region within the MELK promoter that did not map to the p53 consensus response elements, but to a region containing a FOXM1-binding site. Consistent with this result, knockdown of FOXM1 reduced MELK expression in p53-mutant TNBC cells and expression of wild-type p53 reduced FOXM1 expression. ChIP assays demonstrated that expression of wild-type p53 reduces binding of E2F1 (a critical transcription factor controlling FOXM1 expression) to the FOXM1 promoter, thereby, reducing FOXM1 expression. These results show that wild-type p53 suppresses FOXM1 expression, and thus MELK expression, through indirect mechanisms. Overall, these studies demonstrate that wild-type p53 represses MELK expression by inhibiting E2F1A-dependent transcription of FOXM1 and that mutation-driven loss of wild-type p53, which frequently occurs in TNBCs, induces MELK expression by suppressing FOXM1 expression and activity in p53-mutant breast cancers.

© The Author(s) 2020.

Keywords: Breast cancer; Transcription

Conflict of interest statement

Competing interestsP.H.B. served as a Scientific Advisory Board Member for the Susan G. Komen for the Cure Foundation (until 2017) and is a holder of GeneTex stock (<1% of the total company stock); ne

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