LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer

Oncogene. 2016 May;35(21):2746-55. doi: 10.1038/onc.2015.340. Epub 2015 Sep 14.


Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Drug Resistance, Neoplasm
  • Estrogen Antagonists / therapeutic use*
  • Female
  • Humans
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects
  • Tamoxifen / pharmacology*
  • Transcriptional Activation
  • Up-Regulation


  • Estrogen Antagonists
  • HOTAIR long untranslated RNA, human
  • RNA, Long Noncoding
  • Receptors, Estrogen
  • Tamoxifen