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Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

Authors Keenen MM, Kim S

Received 13 August 2016

Accepted for publication 23 September 2016

Published 17 November 2016 Volume 2016:8 Pages 211—221


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Professor Pranela Rameshwar

Madeline M Keenen,1 Suwon Kim1,2

1Department of Basic Medical Sciences, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, 2Division of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ, USA

Abstract: Resistance to antiestrogen therapy remains a significant problem in breast cancer. Low expression of inhibitor of growth 4 (ING4) in primary tumors has been correlated with increased rates of recurrence in estrogen receptor-positive (ER+) breast cancer patients, suggesting a role for ING4 in ER signaling. This study provides evidence that ING4 inhibits ER activity. ING4 overexpression increased the sensitivity of T47D and MCF7 ER+ breast cancer cells to hormone deprivation. ING4 attenuated maximal estrogen-dependent cell growth without affecting the dose–response of estrogen. These results indicated that ING4 functions as a noncompetitive inhibitor of estrogen signaling and may inhibit estrogen-independent ER activity. Supportive of this, treatment with fulvestrant but not tamoxifen rendered T47D cells sensitive to hormone deprivation as did ING4 overexpression. ING4 did not affect nuclear ERα protein expression, but repressed selective ER-target gene transcription. Taken together, these results demonstrated that ING4 inhibited estrogen-independent ER activity, suggesting that ING4-low breast tumors recur faster due to estrogen-independent ER activity that renders tamoxifen less effective. This study puts forth fulvestrant as a proposed therapy choice for patients with ING4-low ER+ breast tumors.

Keywords: tamoxifen resistance, transcription repression, PDZK1, TFF1, estrogen independent ERa, fulvestrant

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