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Updated: Mar 10, 2026

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
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Published on: January 7, 2019

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FOXA2 as a SETD1A-Regulated Driver of Tamoxifen Resistance in Breast Cancer

Myeong Ryeo Kim1, Jae Rim Lee1, Xiaohan Zhang2

  • 1Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea.

Oncology Research
|March 9, 2026
PubMed
Abstract

Insights

Tamoxifen resistance in breast cancer involves elevated forkhead box A2 (FOXA2), regulated by SET Domain Containing 1A (SETD1A). Targeting this SETD1A-FOXA2 pathway may overcome endocrine resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tamoxifen is crucial for estrogen receptor (ER) α-positive breast cancer treatment.
  • Tamoxifen resistance is a major clinical obstacle in managing ERα-positive breast cancer.

Purpose of the Study:

  • To investigate the molecular mechanisms of tamoxifen resistance in ERα-positive breast cancer.
  • To elucidate the role of SET Domain Containing 1A (SETD1A) in regulating forkhead box A2 (FOXA2) and its contribution to tamoxifen resistance.

Main Methods:

  • Assessed FOXA2 expression and SETD1A regulation using qPCR, western blotting, transcriptome profiling, and ChIP.
  • Evaluated FOXA2's functional impact on cell proliferation, migration, invasion, and cancer stem cell traits via siRNA.
  • Examined clinical relevance using patient datasets and tissue microarrays.

Main Results:

  • FOXA2 expression was higher in tamoxifen-resistant and ERα-negative cells.
  • SETD1A directly regulated FOXA2 expression, confirmed by transcriptome and ChIP analyses.
  • FOXA2 knockdown reduced proliferation, migration, invasion, and stem cell traits, restoring tamoxifen sensitivity; high FOXA2 correlated with poor survival and tamoxifen unresponsiveness.

Conclusions:

  • Identified FOXA2 as a key mediator of tamoxifen resistance, regulated by SETD1A.
  • The SETD1A-FOXA2 axis represents a potential therapeutic target for overcoming endocrine resistance in breast cancer.
Keywords:
SET domain containing 1ATamoxifen resistancebreast cancercancer stem cellsforkhead box protein A2

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