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Title: Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells
Authors: Pandey, V 
Zhang, M
You, M 
Zhang, W
Chen, R 
Zhang, W
Ma, L
Wu, Z.-S
Zhu, T
Xu, X.Q
Lobie, P.E 
Keywords: cyclin D1
protein bcl 2
small interfering RNA
STAT3 protein
trefoil factor 3
acinar cell
anchorage independent growth
animal experiment
animal model
breast carcinoma
breast epithelium cell
cell proliferation
cell survival
cell viability
cohort analysis
controlled study
gene expression
HMEC-hTERT cell line
human cell
immortalized cell line
immune deficiency
major clinical study
MCF-10AT cell line
MCF-12A cell line
priority journal
protein expression
protein function
regulatory mechanism
transcription regulation
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Pandey, V, Zhang, M, You, M, Zhang, W, Chen, R, Zhang, W, Ma, L, Wu, Z.-S, Zhu, T, Xu, X.Q, Lobie, P.E (2018). Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells. Cell Death and Disease 9 (12) : 1147. ScholarBank@NUS Repository.
Abstract: Trefoil factor 3 (TFF3) expression is positively associated with advanced clinicopathological features of mammary carcinoma (MC). Herein, we provide evidence for a functional role of TFF3 in oncogenic transformation of immortalized, but otherwise normal human mammary epithelial cells (HMECs), namely, HMEC-hTERT, MCF10A, and MCF12A. Forced expression of TFF3 in immortalized-HMECs enhanced cell proliferation, cell survival, anchorage-independent growth, produced highly disorganised three-dimensional (3D) acinar structures and generated tumours in immunocompromised mice. Forced expression of TFF3 in immortalized-HMECs stimulated STAT3 activity that was required for TFF3-stimulated cell proliferation, survival, and anchorage-independent growth. TFF3 specifically utilised STAT3 activity to govern a transcriptional program, which was required for TFF3-stimulated oncogenic transformation of immortalized-HMECs, including transcriptional upregulation of CCND1 and BCL2. siRNA-mediated depletion or functional inhibition of STAT3 significantly inhibited the TFF3-stimulated transcription of CCND1 and BCL2 and oncogenicity in immortalized-HMECs. Furthermore, DOX-inducible expression of TFF3 in HMEC-hTERT cells also permitted anchorage-independent growth and produced disorganized acinar structures in 3D Matrigel culture. Removal of DOX-induced expression of TFF3 in HMEC-hTERT cells, previously grown with DOX, resulted in efficient normalisation of the disorganized acinar architecture and attenuated cell viability in Matrigel culture. Cumulatively, these findings suggest that TFF3 is a potent oncogene and its increased expression along with hTERT in HMECs is sufficient to produce oncogenic transformation. © 2018, The Author(s).
Source Title: Cell Death and Disease
ISSN: 2041-4889
DOI: 10.1038/s41419-018-1177-6
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