Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2

Abstract

Epithelial–mesenchymal transition (EMT) is a complex process which occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role of Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumor progression, and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2/Slug, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer.

Distinctive properties of metastasis-initiating cells

“…2; Cao et al 2011). Mutation, epigenetic silencing, or reduced expression of luminal differentiation factors in the mammary gland (GATA3 and ELF5) has been shown to promote breast cancer metastasis (Kouros-Mehr et al 2008;Chakrabarti et al 2012). RARRES3, which is involved in retinoic acid-induced differentiation signaling, suppresses breast cancer lung metastasis initiation by promoting tumor differentiation (Morales et al 2014).…”

The CD44s splice isoform is a central mediator for invadopodia activity

“…Female Athymic nude mice (NCI) at age 4-6 weeks were used to test lung metastasis development with LM2 and corresponding sublines. Lateral tail vein intravenous injection of tumor cells was performed as described (Chakrabarti et al, 2012). For luciferase-labeled LM2 cells, the development of metastases was monitored by using BLI with the IVIS Imaging System (Caliper Life Sciences) and analyzed with Living Image software (Caliper Life Sciences) as described previously (Chakrabarti et al, 2012).…”

Moving towards totipotency without a single miR-acle

“…For both the teratoma and embryoid bodies (EBs) generated from miR-34a -/-pluripotent stem cells, marker levels of pluripotency derivative layers remained normal, implying that the cells kept their pluripotency, while a significant increase in key trophectodermal markers, such as Cdx2 and Elf5, was observed. Of note, these two key genes are also implicated in formation of other organs such as intestine [7] and mammary gland [8] …”