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Updated: Jul 17, 2025

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

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MicroRNA regulation of the serine synthesis pathway in endocrine-resistant breast cancer cells

Belinda J Petri1, Kellianne M Piell1, Ali E Wilt1

  • 1Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine Louisville, Kentucky, USA.

Endocrine-Related Cancer
|August 31, 2023
PubMed

Insights

The RNA binding protein HNRNPA2B1 (A2B1) promotes endocrine resistance in ER+ breast cancer by downregulating specific miRNAs that control serine synthesis enzymes. Restoring these miRNAs re-sensitizes cancer cells to therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Estrogen receptor α (ER+) breast cancer with metastatic disease shows improved survival with combination therapies, yet acquired endocrine resistance mechanisms are not fully understood.
  • The RNA binding protein HNRNPA2B1 (A2B1), an N(6)-methyladenosine (m6A) reader, is upregulated in endocrine-resistant ER+ breast cancer cells.
  • Increased expression of serine synthesis pathway (SSP) enzymes, PSAT1 and PHGDH, correlates with poor outcomes in ER+ breast cancer patients treated with tamoxifen.

Purpose of the Study:

  • To investigate the role of HNRNPA2B1 (A2B1) in acquired endocrine resistance in ER+ breast cancer.
  • To elucidate the molecular mechanisms linking A2B1, miRNA dysregulation, and the serine synthesis pathway (SSP) in endocrine resistance.
  • To determine if restoring specific miRNAs can overcome endocrine resistance in ER+ breast cancer cells.

Main Methods:

  • Comparative analysis of HNRNPA2B1 (A2B1) expression in endocrine-sensitive versus resistant ER+ breast cancer cells.
  • miRNA sequencing (miRNA-seq) to identify miRNAs affected by A2B1 overexpression.
  • Dual luciferase assays to confirm miRNA targeting of PSAT1 and PHGDH 3'UTRs.
  • Assessment of tamoxifen (TAM) sensitivity following A2B1 overexpression or miRNA transfection.

Main Results:

  • Stable overexpression of A2B1 in MCF-7 cells increased PSAT1 and PHGDH expression and induced endocrine resistance.
  • Four miRNAs (miR-145-5p, miR-424-5p, miR-34b-5p, miR-876-5p) were identified as downregulated in A2B1-overexpressing cells and directly target PSAT1 and PHGDH.
  • Lower expression of these specific miRNAs in resistant cell lines correlated with increased PSAT1 and PHGDH levels.
  • Transient transfection of these miRNAs restored endocrine therapy sensitivity in resistant ER+ breast cancer cells.

Conclusions:

  • Decreased expression of A2B1-regulated miRNAs contributes to endocrine resistance in ER+ breast cancer.
  • Upregulation of the serine synthesis pathway (SSP) via A2B1-mediated miRNA suppression promotes tumor progression.
  • Targeting the A2B1-miRNA-SSP axis offers a potential therapeutic strategy to overcome endocrine resistance in ER+ breast cancer.
Keywords:
HNRNPA2B1endocrine resistancemiRNAphosphoglycerate dehydrogenasephosphoserine aminotransferase 1serine synthesis

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