Research Papers:

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 and Peter E. Lobie _

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Oncotarget. 2017; 8:77268-77291. https://doi.org/10.18632/oncotarget.20461

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Vijay Pandey1, Min Zhang3, Qing-Yun Chong1, Mingliang You1, Ainiah Rushdiana Raquib1, Amit K. Pandey1, Dong-Xu Liu8, Liang Liu6,7, Lan Ma5, Sudhakar Jha1, Zheng-Sheng Wu4, Tao Zhu3 and Peter E. Lobie1,2,5

1Cancer Science Institute of Singapore, National University of Singapore, Singapore

2Department of Pharmacology, National University of Singapore, Singapore

3Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, P.R. China

4Department of Pathology, Anhui Medical University, Hefei, P.R China

5Tsinghua Berkeley Shenzhen Institute, Division of Life Sciences & Health, Tsinghua University Graduate School, Shenzhen, P.R China

6Department of Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R China

7Department of Radiology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R China

8School of Science, Auckland University of Technology, Auckland, New Zealand

Correspondence to:

Peter E. Lobie, email: [email protected]

Tao Zhu, email: [email protected]

Keywords: TFF3, tamoxifen, endometrial carcinoma, breast cancer, oestrogen receptor (ER)

Received: February 23, 2017     Accepted: July 16, 2017     Published: August 24, 2017


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 receptor-positive (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.

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