Inhibition of antiestrogen-promoted pro-survival autophagy and tamoxifen resistance in breast cancer through vitamin d receptor

Ye Li, Katherine L. Cook, Wei Yu, Lu Jin, Kerrie B. Bouker, Robert Clarke, Leena Hilakivi-Clarke

Research output: Contribution to journalArticlepeer-review

Abstract

We determined how vitamin D receptor (VDR) is linked to disease outcome in estrogen receptor-positive (ER+) breast cancer patients treated with tamoxifen (TAM). Breast cancer patients (n = 581) in four different datasets were divided into those expressing higher (above median) and lower levels of VDR in pretreatment ER+ tumors. Across all datasets, TAM-treated patients with higher pretreatment tumor VDR expression exhibited significantly longer recurrence-free survival. Ingenuity pathway analysis identified autophagy and unfolded protein response (UPR) as top differentially expressed pathways between high and low VDR-expressing ER+ cancers. Activation of VDR with vitamin D (VitD), either calcitriol or its synthetic analog EB1089, sensitized MCF-7derived, antiestrogen-resistant LCC9 human breast cancer cells to TAM, and attenuated increased UPR and pro-survival autophagy. Silencing of VDR blocked these effects through the IRE1α-JNK pathway. Further, silencing of VDR impaired sensitivity to TAM in antiestrogen-responsive LCC1 cells, and prevented the effects of calcitriol and EB1089 on UPR and autophagy. In a preclinical mouse model, dietary VitD supplementation induced VDR activation and reduced carcinogen-induced ER+ mammary tumor incidence. In addition, IRE1α-JNK signaling was downregulated and survival autophagy was inhibited in mammary tumors of VitD-supplemented mice. Thus, activation of VDR is predictive of reduced risk of breast cancer recurrence in ER+ patients, possibly by inhibiting antiestrogen-promoted pro-survival autophagy.

Original languageEnglish (US)
Article number1715
JournalNutrients
Volume13
Issue number5
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
Funding: This research was funded by the NCI, R01-CA164384 (to L. Hilakivi-Clarke), U54-CA149147 (to R. Clarke) and P30-CA51008 (to Lombardi Comprehensive Cancer Center; funding for Shared Resources).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Autophagy
  • Breast cancer
  • Recurrence-free survival
  • Tamoxifen
  • Vitamin D analogs
  • Vitamin D receptor

PubMed: MeSH publication types

  • Journal Article

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