Rationale: The transcription factor ELF5 is an essential mediator of cell fate in the mammary gland. ELF5 also suppresses estrogen sensitivity and drives anti-estrogen resistance in breast cancer cells. ELF5 has 4 splice variants, which produce 2 full-length proteins with unique N-termini (ESE-2a/ESE-2b) and 2 short proteins, which lack the internal pointed/SAM domain (isoforms 3/4). The functions of these different isoforms in cancer are not known.
Objective: To examine the expression and function of ELF5 splice variants in normal and malignant tissues.
Methods and Results: Expression of ELF5 variants was analysed using RNA-seq data from The Cancer Genome Atlas. Splice variants were differentially expressed among normal tissues and the levels and proportions of variants were disrupted in tumours. A subset of cervical, colon and uterine carcinomas, for example, had increased ELF5 levels, while ELF5 was down-regulated in almost all kidney carcinomas. ELF5 (primarily ESE-2b) was generally lower in breast cancers compared to normal tissues but was over-expressed in the basal (‘ER-negative’) subtype.
We generated doxycycline-inducible breast cancer cell models to study the functional effects of ELF5 splice variants. Forced expression of ESE-2a or ESE-2b in T47D cells had similar effects on cell phenotype and gene expression, and resulted in decreased proliferation, altered breast cancer subtype and attenuated endocrine response.
Conclusions: Expression of ELF5 splice variants is tissue-specific and is dysregulated in many cancers. The breast expresses high ELF5, which is further increased in basal breast cancer. In the luminal breast cancer cell line T47D, both full-length isoforms have similar functional effects.