Determining the Role of ETS Factor ELF3/ESE-1 in the Normal and Malignant Prostate - European Medical Journal

Determining the Role of ETS Factor ELF3/ESE-1 in the Normal and Malignant Prostate

1 Mins
Oncology
Authors:
Leanne K. Archer, Fiona M. Frame, *Norman J. Maitland
Disclosure:

The authors have declared no conflicts of interest.

Support:

This research was funded by a grant from Prostate Cancer UK.

Citation:
EMJ Oncol. ;5[1]:48-49. Abstract Review No. AR7.
Keywords:
ELF3 gene, ETS factors, prostate cancer

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Prostate epithelial cells exist as a differentiation hierarchy, which is structured as two layers. The basal layer is the more proliferative compartment of the epithelium and is comprised of three different cell types: stem cells, transit amplifying cells, and committed basal (CB) cells. CB cells differentiate to form the luminal layer of the epithelium, which consists of terminally differentiated, secretory luminal cells. In prostate cancer, epithelial differentiation is deregulated, resulting in the growth and expansion of the luminal population. Treatment strategies for advanced prostate cancer currently focus on androgen ablation therapies, which target the androgen-sensitive luminal population. However, evidence suggests that prostate cancer arises from the basal population, which is not targeted by current treatments.

In prostate cancer, the most prevalent genetic abnormality is the TMPRSS2:ERG fusion. ERG is a member of the ETS factor family, members of which are widely known to be involved in several types of cancers, including leukaemias. The aim of this study was to define the role of the epithelial-specific ETS transcription factor ELF3 in normal prostate epithelium, as well as its role in prostate cancer. ELF3 has been described as both a driver and repressor of cancer in different tissues, including prostate cancer. Similar findings for other ETS factors suggest that ELF3 may function in a highly cell type-dependent, and context-dependent, manner.1

A gene expression microarray, with RNA derived from benign and cancerous prostate tissue, indicated that ELF3 was significantly more highly expressed in the CB cell fraction compared to stem cells, regardless of pathological diagnosis. At the protein level, consistently higher ELF3 expression was seen in the CB cell population compared to the less differentiated transit amplifying cells, and ELF3 was undetectable in luminal epithelial cells or stroma, by both immunohistochemistry and western blot.

BPH-1 (benign) and PC3 (cancer) cell lines were chosen as suitable ELF3-expressing basal cell models to investigate the effects of knockdown of ELF3. Using small interfering-RNA transfection, ELF3 knockdown reduced the migration, clonogenicity, and viability of prostate epithelial cells over time, regardless of origin. A gene expression microarray performed on BPH-1 and PC3 cells after ELF3 knockdown, revealed significant changes related to control of the cell cycle, which was consistent with the functional changes seen. Changes in cell cycle protein expression matched the RNA expression results. Preliminary experiments suggest ELF3 knockdown causes an arrest at the G2 phase, which equally correlates with the specific gene changes seen in the microarray.

Current work, including ELF3 overexpression and ELF3 knockdown in primary prostate epithelial cultures derived from patient tumour biopsies, will provide clinically relevant evidence as to the precise role of ELF3 in the prostate. Further experiments are also being carried out using quantitative phase imaging to analyse the rapid, real-time changes in cells after ELF3 expression manipulation. What emerges from these studies is that rather than acting as a facilitator of tumour progression, ELF3 appears to play a prominent role in prostate epithelial cell differentiation.

References
Archer LK et al. Stem cells and the role of ETS transcription factors in the differentiation hierarchy of normal and malignant prostate epithelium. J Steroid Biochem Mol Biol. 2017;166:68-83.

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