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Cancer Res. 2013 Sep 1;73(17):5556-68. doi: 10.1158/0008-5472.CAN-13-0013. Epub 2013 Aug 16.

Hbo1 is a cyclin E/CDK2 substrate that enriches breast cancer stem-like cells.

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1
Departments of Experimental Radiation Oncology, Radiation Oncology, and Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0066, Houston, TX77030, USA.

Abstract

Expression of cyclin E proteolytic cleavage products, low-molecular weight cyclin E (LMW-E), is associated with poor clinical outcome in patients with breast cancer and it enhances tumorigenecity in mouse models. Here we report that LMW-E expression in human mammary epithelial cells induces an epithelial-to-mesenchymal transition phenotype, increases the CD44(hi)/CD24(lo) population, enhances mammosphere formation, and upregulates aldehyde dehydrogenase expression and activity. We also report that breast tumors expressing LMW-E have a higher proportion of CD44(hi)/CD24(lo) tumor cells as compared with tumors expressing only full-length cyclin E. In order to explore how LMW-E enriches cancer stem cells in breast tumors, we conducted a protein microarray analysis that identified the histone acetyltransferase (HAT) Hbo1 as a novel cyclin E/CDK2 substrate. The LMW-E/CDK2 complex phosphorylated Hbo1 at T88 without affecting its HAT activity. When coexpressed with LMW-E/CDK2, wild-type Hbo1 promoted enrichment of cancer stem-like cells (CSC), whereas the T88 Hbo1 mutant reversed the CSC phenotype. Finally, doxorubicin and salinomycin (a CSC-selective cytotoxic agent) synergized to kill cells expressing LMW-E, but not full-length cyclin E. Collectively, our results suggest that the heightened oncogenecity of LMW-E relates to its ability to promote CSC properties, supporting the design of therapeutic strategies to target this unique function.

PMID:
23955388
PMCID:
PMC3773499
DOI:
10.1158/0008-5472.CAN-13-0013
[Indexed for MEDLINE]
Free PMC Article

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