title: 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 ER alpha-negative cases). In ER alpha-positive cases, levels of XBP-1U mRNA correlated with ER alpha 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: ER alpha-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 ER alpha-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.
authors.affiliation: Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Liverpool, United Kingdom. Michael.Davies@liverpool.ac.uk
authors.forename: Michael P A
authors.initials: MP
authors.lastname: Davies
authors.forename: Dong Liu
authors.initials: DL
authors.lastname: Barraclough
authors.forename: Ceri
authors.initials: C
authors.lastname: Stewart
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Joyce
authors.forename: Richard M
authors.initials: RM
authors.lastname: Eccles
authors.forename: Roger
authors.initials: R
authors.lastname: Barraclough
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rudland
authors.forename: David Ross
authors.initials: DR
authors.lastname: Sibson
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016017:Odds Ratio; D016016:Proportional Hazards Models; D017510:Protein Folding; D019154:Protein Splicing; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use*; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D013629:Tamoxifen