Current endocrine therapies are quite effective in treating ERα+ breast cancer (BC) tumors, but resistance to treatment is common. Xenografts and phase II clinical trials revealed that fasting-mimicking diet (FMD) enhances endocrine treatment efficacy, but the underlying mechanisms thereof remain unclear. The goal of this study is to understand the mechanisms underlying the beneficial effects of fasting on endocrine treatment in BC. MCF-7 cells were xenografted in mice, and animals were treated with tamoxifen alone, or combined with FMD. Tumors were isolated and analyzed for 1) RNA-seq, 2) proteomics, 3) phosphoproteomics, 4) ChIP-seq for ERα and H3K27ac, 5) RIME for ERα, and 6) immunohistochemistry. RIME for ER showed decreased binding to ribosomal and mRNA splicing proteins in animals treated with endocrine therapy together with FMD, which coincided with a dramatic loss of spliced XBP1 levels on immunohistochemistry and MCL1 protein levels. Furthermore, ChIP-seq analyses revealed an epigenetic plasticity, specifically in fasted animals treated with tamoxifen, through loss of stress-activated AP-1 sites and a gain of tumor suppressor GR and PR sites. Jointly, our data reveal that fasting abrogates the tamoxifen-induced stress response in tumor cells on translational and epigenetic scale, providing mechanistic clues for clinically promising, yet poorly understood, lifestyle based intervention in BC.