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

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

doi:10.3390/nu13051715

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-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.

Highlights

In 2020, breast cancer surpassed lung cancer as the most commonly diagnosed cancer worldwide, with approximately 2.3 million women diagnosed with this disease [1]
In four independent databases consisting of a total of 581 ER+ breast cancer patients treated with TAM, higher pretreatment expression of vitamin D receptor (VDR) in the tumors was predictive of significantly longer relapse-free survival (RFS), compared with patients whose tumors expressed lower levels of VDR (Figure 1A–D)
High VDR Expression is Associated with Longer Recurrence-Free Survival in TAM-Treated

Summary

Introduction

In 2020, breast cancer surpassed lung cancer as the most commonly diagnosed cancer worldwide, with approximately 2.3 million women diagnosed with this disease [1]. 70% of breast cancers are estrogen receptor positive (ER+) [2,3], and ER activation is associated with breast cancer development and progression. A major clinical challenge is that the 5-year survival rate for invasive breast cancer is 90%, over 50% of those with non-metastatic, lymph node-positive, ER+ breast cancer at diagnosis will recur within. UPR is activated in normal cells under conditions such as oxidative stress, nutrient deprivation, or hypoxia, leading to the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum [7]. UPR remains chronically activated due to constant stress. Increased pro-survival autophagy is causally linked to endocrine resistance in breast cancer [10,11]. Autophagy inhibits cancer development but once tumors are present, autophagy helps cancer cells to survive and grow [13]

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Results

Conclusion