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2016 ; 18
(5
): 317-327
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The Heterodimeric TWIST1-E12 Complex Drives the Oncogenic Potential of TWIST1 in
Human Mammary Epithelial Cells
#MMPMID27237323
Jacqueroud L
; Bouard C
; Richard G
; Payen L
; Devouassoux-Shisheboran M
; Spicer DB
; Caramel J
; Collin G
; Puisieux A
; Tissier A
; Ansieau S
Neoplasia
2016[May]; 18
(5
): 317-327
PMID27237323
show ga
The TWIST1 embryonic transcription factor displays biphasic functions during the
course of carcinogenesis. It facilitates the escape of cells from
oncogene-induced fail-safe programs (senescence, apoptosis) and their consequent
neoplastic transformation. Additionally, it promotes the
epithelial-to-mesenchymal transition and the initiation of the metastatic spread
of cancer cells. Interestingly, cancer cells recurrently remain dependent on
TWIST1 for their survival and/or proliferation, making TWIST1 their Achilles'
heel. TWIST1 has been reported to form either homodimeric or heterodimeric
complexes mainly in association with the E bHLH class I proteins. These complexes
display distinct, sometimes even antagonistic, functions during development and
unequal prometastatic functions in prostate cancer cells. Using a tethered dimer
strategy, we successively assessed the ability of TWIST1 dimers to cooperate with
an activated version of RAS in human mammary epithelial cell transformation, to
provide mice with the ability to spontaneously develop breast tumors, and lastly
to maintain a senescence program at a latent state in several breast cancer cell
lines. We demonstrate that the TWIST1-E12 complex, unlike the homodimer, is an
oncogenic form of TWIST1 in mammary epithelial cells and that efficient binding
of both partners is a prerequisite for its activity. The detection of the
heterodimer in human premalignant lesions by a proximity ligation assay, at a
stage preceding the initiation of the metastatic cascade, is coherent with such
an oncogenic function. TWIST1-E protein heterodimeric complexes may thus
constitute the main active forms of TWIST1 with regard to senescence inhibition
over the time course of breast tumorigenesis.