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Inhibition of Antiestrogen-Promoted Pro-Survival Autophagy and Tamoxifen Resistance in Breast Cancer through Vitamin D Receptor

Department of Oncology, Georgetown University, Washington, DC 20057, USA
*
Author to whom correspondence should be addressed.
Current address: The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Current address: Department(s) of Surgery and Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
§
Current address: The Hormel Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Academic Editor: William B. Grant
Nutrients 2021, 13(5), 1715; https://doi.org/10.3390/nu13051715
Received: 8 April 2021 / Revised: 11 May 2021 / Accepted: 12 May 2021 / Published: 19 May 2021
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-7-derived, 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. View Full-Text
Keywords: breast cancer; recurrence-free survival; tamoxifen; vitamin D receptor; vitamin D analogs; autophagy breast cancer; recurrence-free survival; tamoxifen; vitamin D receptor; vitamin D analogs; autophagy
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MDPI and ACS Style

Li, Y.; Cook, K.L.; Yu, W.; Jin, L.; Bouker, K.B.; Clarke, R.; Hilakivi-Clarke, L. Inhibition of Antiestrogen-Promoted Pro-Survival Autophagy and Tamoxifen Resistance in Breast Cancer through Vitamin D Receptor. Nutrients 2021, 13, 1715. https://doi.org/10.3390/nu13051715

AMA Style

Li Y, Cook KL, Yu W, Jin L, Bouker KB, Clarke R, Hilakivi-Clarke L. Inhibition of Antiestrogen-Promoted Pro-Survival Autophagy and Tamoxifen Resistance in Breast Cancer through Vitamin D Receptor. Nutrients. 2021; 13(5):1715. https://doi.org/10.3390/nu13051715

Chicago/Turabian Style

Li, Ye, Katherine L. Cook, Wei Yu, Lu Jin, Kerrie B. Bouker, Robert Clarke, and Leena Hilakivi-Clarke. 2021. "Inhibition of Antiestrogen-Promoted Pro-Survival Autophagy and Tamoxifen Resistance in Breast Cancer through Vitamin D Receptor" Nutrients 13, no. 5: 1715. https://doi.org/10.3390/nu13051715

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