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Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells

Madeline M Keenen1, Suwon Kim2

  • 1Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ.

Breast Cancer (Dove Medical Press)
|November 30, 2016
PubMed

Insights

Inhibitor of Growth 4 (ING4) inhibits estrogen receptor (ER) activity, potentially improving antiestrogen therapy effectiveness. Low ING4 levels in ER+ breast tumors may drive recurrence by promoting estrogen-independent ER activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Antiestrogen therapy resistance is a major challenge in breast cancer treatment.
  • Low expression of inhibitor of growth 4 (ING4) in primary tumors correlates with recurrence in estrogen receptor-positive (ER+) breast cancer.
  • ING4's role in ER signaling suggests a potential therapeutic target.

Purpose of the Study:

  • To investigate the role of ING4 in estrogen receptor (ER) activity and its implications for antiestrogen therapy resistance.
  • To determine if ING4 functions as an inhibitor of ER signaling in ER+ breast cancer cells.
  • To explore the therapeutic potential of targeting ING4 in breast cancer treatment.

Main Methods:

  • Overexpression of ING4 in T47D and MCF7 ER+ breast cancer cell lines.
  • Assessment of cell sensitivity to hormone deprivation and estrogen dose-response.
  • Analysis of ERα protein expression and ER-target gene transcription.
  • Treatment of cells with fulvestrant and tamoxifen.

Main Results:

  • ING4 overexpression increased sensitivity to hormone deprivation in ER+ breast cancer cells.
  • ING4 attenuated maximal estrogen-dependent cell growth without altering estrogen dose-response.
  • ING4 repressed selective ER-target gene transcription and inhibited estrogen-independent ER activity.
  • Fulvestrant, but not tamoxifen, sensitized cells to hormone deprivation, similar to ING4 overexpression.

Conclusions:

  • ING4 acts as a noncompetitive inhibitor of estrogen signaling, including estrogen-independent ER activity.
  • Low ING4 expression in ER+ breast tumors may lead to faster recurrence due to enhanced estrogen-independent ER activity, reducing tamoxifen efficacy.
  • Fulvestrant is proposed as a potential therapy for ING4-low ER+ breast tumors.
Keywords:
PDZK1TFF1estrogen independent ERafulvestranttamoxifen resistancetranscription repression

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