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miR-1271 inhibits ERα expression and confers letrozole resistance in breast cancer

Tao Yu1,2, Hai-Ru Yu2, Jia-Yi Sun2

  • 1Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, P.R.China.

Oncotarget
|January 2, 2018
PubMed

Insights

MicroRNA-1271 (miR-1271) downregulation contributes to letrozole resistance in breast cancer by increasing DNA damage-inducible transcript 3 (DDIT3) and reducing estrogen receptor α (ERα). Restoring miR-1271 can re-sensitize breast cancer to letrozole.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Endocrine-resistant breast cancer (BCa) is characterized by reduced estrogen receptor α (ERα) expression through poorly understood mechanisms.
  • Letrozole resistance is a significant clinical challenge in BCa treatment, necessitating a deeper understanding of its molecular underpinnings.

Purpose of the Study:

  • To elucidate the role of microRNA-1271 (miR-1271) in the development of letrozole resistance in breast cancer.
  • To investigate the molecular mechanisms by which miR-1271 influences ERα expression and drug sensitivity.

Main Methods:

  • Quantification of miR-1271 and DDIT3 mRNA levels in letrozole-resistant and sensitive BCa tissues and cells.
  • Chromatin immunoprecipitation assays to determine direct targeting of the DDIT3 gene by miR-1271.
  • Functional studies involving reintroduction of miR-1271 into resistant cells to assess its impact on ERα levels and drug sensitivity.
  • Analysis of DDIT3's role as a corepressor of ESR1 transcription.

Main Results:

  • miR-1271 was significantly downregulated in letrozole-resistant BCa tissues and cells.
  • miR-1271 directly targets the DDIT3 gene, with its expression inversely correlated to DDIT3 mRNA levels.
  • Restoring miR-1271 inhibited DDIT3, increased ERα levels, and restored sensitivity to letrozole in BCa cells.
  • DDIT3 deregulation promoted letrozole resistance by repressing ESR1 transcription.

Conclusions:

  • The miR-1271/DDIT3/ERα signaling axis is critically disrupted in letrozole-resistant breast cancer.
  • Downregulation of miR-1271 is a key driver of letrozole resistance, mediated by DDIT3-induced repression of ERα.
  • Targeting the miR-1271/DDIT3 pathway offers a potential therapeutic strategy to overcome endocrine resistance in BCa.
Keywords:
DDIT3breast cancerestrogen receptorletrozolemiR-1271

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