Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells

Vijay Pandey, Min Zhang, Qing Yun Chong, Mingliang You, Ainiah Rushdiana Raquib, Amit K. Pandey, Dong Xu Liu, Liang Liu, Lan Ma, Sudhakar Jha, Zheng Sheng Wu, Tao Zhu, Peter E. Lobie

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Tamoxifen (TAM) is widely used as an adjuvant therapy for women with breast cancer (BC). However, TAM possesses partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial carcinoma (EC). The molecular mechanism for these observations is not well understood. Herein, we demonstrated that forced expression of Trefoil factor 3 (TFF3), in oestrogen receptorpositive (ER+) EC cells significantly increased cell cycle progression, cell survival, anchorage-independent growth, invasiveness and tumour growth in xenograft models. Clinically, elevated TFF3 protein expression was observed in EC compared with normal endometrial tissue, and its increased expression in EC was significantly associated with myometrial invasion. TAM exposure increased expression of TFF3 in ER+ EC cells and its elevated expression resulted in increased oncogenicity and invasiveness. TAM-stimulated expression of TFF3 in EC cells was associated with hypomethylation of the TFF3 promoter sequence and c-JUN/SP1-dependent transcriptional activation. In addition, small interfering (si) RNA-mediated depletion or polyclonal antibody inhibition of TFF3 significantly abrogated oncogenicity and invasiveness in EC cells consequent to TAM induction or forced expression of TFF3. Hence, TAM-stimulated upregulation of TFF3 in EC cells was critical in promoting EC progression associated with TAM treatment. Importantly, inhibition of TFF3 function might be an attractive molecular modality to abrogate the stimulatory effects of TAM on endometrial tissue and to limit the progression of EC.

Original languageEnglish (US)
Pages (from-to)77268-77291
Number of pages24
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - 2017

Keywords

  • Breast cancer
  • Endometrial carcinoma
  • Oestrogen receptor (ER)
  • TFF3
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology

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