Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells. Issue 12 (December 2018)

• Record Type: Journal Article
• Authors: Pandey, Vijay; Zhang, Min; You, Mingliang; Zhang, Weijie; Chen, Rumei; Zhang, Wei; Ma, Lan; Wu, Zheng-Sheng; Zhu, Tao; Xu, Xiu; Lobie, Peter
• Is Part Of: Cell death and disease. Volume 9:Issue 12(2018)
• Page Start: 1
• Page End: 18
• Publication Date: 2018-12
• Subjects: Cell death -- Periodicals; Apoptosis -- Periodicals; 571.936
• DOI: 10.1038/s41419-018-1177-6
• Languages: English
• ISSNs: 2041-4889

Abstract

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 ofimmortalized, but otherwise normal human mammary epithelial cells (HMECs), namely, HMEC-hTERT, MCF10A, and MCF12A. Forced expression of TFF3 inimmortalized -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 inimmortalized -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 ofimmortalized -HMECs, including transcriptional upregulation ofCCND1 andBCL2 .siRNA -mediated depletion or functional inhibition of STAT3 significantly inhibited the TFF3-stimulated transcription ofCCND1 andBCL2 and oncogenicity inimmortalized -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 withhTERT in HMECs is sufficient to produce oncogenic transformation.