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Updated: Jun 16, 2025

An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
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An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation

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Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer

Sarah Naomi Olsen1, Bryn Anderson1, Charlie Hatton1

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02215, USA.

Cell Reports. Medicine
|June 14, 2025
PubMed

Insights

Combining KAT6A/B and Menin inhibitors shows synergistic effects against estrogen receptor-positive breast cancer. This dual inhibition targets ER-driven gene expression, offering a promising therapeutic strategy for endocrine-resistant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • KAT6A histone acetyltransferase is a potential therapeutic target in cancers, including ER+ breast cancer.
  • Menin acts as a chromatin adaptor and its role in KAT6A/B inhibitor response is under investigation.

Purpose of the Study:

  • To identify regulators of KAT6A/B inhibitor response using CRISPR screens.
  • To investigate the synergistic effects of combined KAT6A/B and Menin inhibition in breast cancer.

Main Methods:

  • CRISPR screening to identify chromatin adaptors.
  • Co-treatment assays with KAT6A/B and Menin inhibitors.
  • Analysis of gene expression and protein localization at target gene promoters.

Main Results:

  • Menin was identified as a regulator of KAT6A/B inhibitor response.
  • Combined KAT6A/B and Menin inhibition demonstrated synergistic anti-proliferative effects in ER+ breast cancer lines.
  • This combination therapy effectively reduced ER-driven gene expression and showed efficacy in preclinical models of endocrine resistance.

Conclusions:

  • KAT6A and Menin cooperatively regulate ER-driven gene expression, impacting ESR1 levels and promoter activity.
  • Combined KAT6A/B and Menin inhibition offers a potential therapeutic strategy for ER+ breast cancer, including endocrine-resistant forms.
  • The manageable toxicity profiles of these inhibitors in clinical trials highlight their therapeutic potential.
Keywords:
ERKAT6AMeninbreast cancerchromatinestrogen receptor

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