A miR-770-5p/XBP1-driven pathway controls ESR1 expression and tamoxifen response in luminal breast cancer.

Background: Cancer cells employ various adaptive mechanisms to withstand stressors, with one notable pathway being the unfolded protein response (UPR), crucial in fostering endocrine resistance within ER-positive breast cancer. Investigating miRNAs within tumors holds promise for identifying key miRNA-gene interactions pivotal for tumor characteristics like proliferation and resistance to treatment. Notably, XBP1 emerges as a pivotal player in UPR within the endoplasmic reticulum, particularly through the inositol-requiring enzyme 1 (IRE1α) - the X-box-binding protein 1 (XBP1) pathway, presenting a compelling target for clinical intervention. In this study, I explore the regulatory role of miR-770-5p in modulating XBP1 expression and its potential as a therapeutic target in luminal breast cancer.

Methods and results: The role of XBP1 in cancer cell pathogenesis has been investigated using bioinformatics tools to analyze its expression in breast cancer samples and its association with clinical outcomes. The relationship between miR-770-5p and XBP1 was further explored through bioinformatics analysis and ROC plot assessment. qRT-PCR and bioinformatics data confirmed the negative correlation between miR-770-5p and XBP1, particularly in Luminal A subtype with wild-type p53. My results demonstrated that miR-770-5p targets XBP1, inhibiting its spliced form and reducing its downstream transcriptional activity. Moreover, I found that miR-770-5p can modulate tamoxifen sensitivity by influencing the XBP1/ESR1 axis in breast cancer cells. Overexpression of miR-770-5p led to decreased ESR1 levels, enhancing tamoxifen efficacy and suggesting a potential novel therapeutic approach for luminal subtype breast cancer.

Conclusions: miR-770-5p has a growth-inhibitory function in luminal breast cancer, where its suppression of XBP1 contributes to the increased sensitivity to tamoxifen.