Expression and splicing of the unfolded protein response gene XBP‐1 are significantly associated with clinical outcome of endocrine‐treated breast cancer

Abstract

X‐box binding protein 1 (XBP‐1) is stimulated by endoplasmic reticulum stress as part of the unfolded protein response (UPR), which can promote apoptosis or cell survival. Non‐conventional splicing, stimulated during the UPR, converts mRNA for “unspliced” XBP‐1U to “spliced” XBP‐1S mRNA. XBP‐1 mRNA is oestrogen‐responsive, but XBP‐1S confers oestrogen independence and anti‐oestrogen resistance to breast cancer cell lines. We therefore evaluated XBP‐1 mRNA splicing as a factor in response of breast cancer patients to endocrine treatment. XBP‐1 isoforms were measured by quantitative RT‐PCR in 100 primary breast cancer patients treated with adjuvant tamoxifen (including 30 ERα‐negative cases). In ERα‐positive cases, levels of XBP‐1U mRNA correlated with ERα mRNA levels and were lower in grade 3 tumors. Higher levels of XBP‐1U mRNA were significantly associated with breast cancer survival (Log‐rank p = 0.002; Cox hazard ratio (HR) 0.2, p = 0.005), independent of grade, size, nodal status and progesterone receptor status. However, in the full cohort, higher ratios of XBP‐1S/XBP‐1U mRNA (indicating enhanced splicing) were associated with poor survival (Log‐rank p = 0.03; Cox HR 2.3, p = 0.03) and related factors: ERα‐negative status, progesterone receptor negative status, grade 3 tumors and greater proliferation. Significant associations with poor outcome were also seen for XBP‐1 splicing in ERα‐positive cases. Our findings, that XBP‐1 isoforms are differently associated with outcome of endocrine therapy for patients, can be explained by higher levels of dominant‐negative XBP‐1U favouring apoptosis of tumor cells and higher levels of XBP‐1S increasing tumor survival.