PURPOSE: Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. MATERIALS AND METHODS: We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. RESULTS: We identified a strong positive association between the XBP1 gene signature and estrogen receptor-positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. CONCLUSION: These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment.
PURPOSE: Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. MATERIALS AND METHODS: We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. RESULTS: We identified a strong positive association between the XBP1 gene signature and estrogen receptor-positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. CONCLUSION: These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment.
Authors: B S Finlin; C L Gau; G A Murphy; H Shao; T Kimel; R S Seitz; Y F Chiu; D Botstein; P O Brown; C J Der; F Tamanoi; D A Andres; C M Perou Journal: J Biol Chem Date: 2001-08-31 Impact factor: 5.157
Authors: C M Perou; T Sørlie; M B Eisen; M van de Rijn; S S Jeffrey; C A Rees; J R Pollack; D T Ross; H Johnsen; L A Akslen; O Fluge; A Pergamenschikov; C Williams; S X Zhu; P E Lønning; A L Børresen-Dale; P O Brown; D Botstein Journal: Nature Date: 2000-08-17 Impact factor: 49.962
Authors: S Tozlu; I Girault; S Vacher; J Vendrell; C Andrieu; F Spyratos; P Cohen; R Lidereau; I Bieche Journal: Endocr Relat Cancer Date: 2006-12 Impact factor: 5.678
Authors: Richard M Neve; Koei Chin; Jane Fridlyand; Jennifer Yeh; Frederick L Baehner; Tea Fevr; Laura Clark; Nora Bayani; Jean-Philippe Coppe; Frances Tong; Terry Speed; Paul T Spellman; Sandy DeVries; Anna Lapuk; Nick J Wang; Wen-Lin Kuo; Jackie L Stilwell; Daniel Pinkel; Donna G Albertson; Frederic M Waldman; Frank McCormick; Robert B Dickson; Michael D Johnson; Marc Lippman; Stephen Ethier; Adi Gazdar; Joe W Gray Journal: Cancer Cell Date: 2006-12 Impact factor: 31.743