Aromatase inhibitor treatment of breast cancer cells increases the expression of let-7f, a microRNA targeting CYP19A1

Yukiko Shibahara, Yasuhiro Miki, Yoshiaki Onodera, Shuko Hata, Monica S.M. Chan, Christopher C.P. Yiu, Tjing Y. Loo, Yasuhiro Nakamura, Jun Ichi Akahira, Takanori Ishida, Keiko Abe, Hisashi Hirakawa, Louis W.C. Chow, Takashi Suzuki, Noriaki Ouchi, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Aromatase inhibitors (AIs) are considered the gold standard of endocrine therapy for oestrogen receptor-positive postmenopausal breast cancer patients. AI treatment was reported to result in marked alterations of genetic profiles in cancer tissues but its detailed molecular mechanisms have not been elucidated. Therefore, we profiled miRNA expression before and after treatment with letrozole in MCF-7 co-cultured with primary breast cancer stromal cells. Letrozole significantly altered the expression profiles of cancer miRNAs in vitro. Among the elevated miRNAs following letrozole treatment, computational analysis identified let-7f , a tumour-suppressor miRNA which targeted the aromatase gene (CYP19A1) expression. Quantitative real-time PCR assay using MCF-7 and SK-BR-3 cells as well as clinical specimens of a neoadjuvant study demonstrated a significant inverse correlation between aromatase mRNA and let-7f expression. In addition, high let-7f expression was significantly correlated with low aromatase protein levels evaluated by both immunohistochemistry and the western blotting method in breast cancer cases. Results of 3'UTR luciferase assay also demonstrated the actual let-7f binding sites in CYP19A1, indicating that let-7f directly targets the aromatase gene. Subsequent WST-8 and migration assays performed in let-7f -transfected MCF-7 and SK-BR-3 cells revealed a significant decrement of their proliferation and migration. These findings all demonstrated that let-7f, a tumour suppressor miRNA in breast cancer, directly targeted the aromatase gene and was restored by AI treatment. Therefore, AIs may exert tumour-suppressing effects upon breast cancer cells by suppressing aromatase gene expression via restoration of let-7f.

Original languageEnglish
Pages (from-to)357-366
Number of pages10
JournalJournal of Pathology
Volume227
Issue number3
DOIs
Publication statusPublished - 2012 Jul

Keywords

  • Aromatase inhibitors
  • Breast cancer
  • CYP19A1
  • Let-7

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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