title: Gene expression profiling of luminal B breast cancers reveals NHERF1 as a new marker of endocrine resistance.
abstract: The luminal B subtype represents a group of high proliferating estrogen receptor positive breast cancers which are associated with a poor prognosis. Genes exclusively expressed in this subtype should help to better understand these tumors. In a finding cohort of 171 breast cancers luminal B specific genes were identified displaying strong expression in highly proliferating Ki-67 positive/ER positive tumors but no expression either in Ki-67 negative/ER positive or in Ki-67 positive/ER negative samples. The clinical relevance of the scaffold protein NHERF1 identified by this strategy was assessed in a total of 3,030 breast cancers. NHERF1 expression was associated with the luminal B subtype both in the finding and validation cohort. A positive correlation of NHERF1 expression with tumor size (P < 0.001), grade (P < 0.001), and HER2 status (P = 0.033) was observed. NHERF1 expression was associated with a worse survival in ER positive breast cancer (P < 0.001) and retained its prognostic value in multivariate analysis. For ER positive samples with low NHERF1 expression a benefit of endocrine therapy was detected (P = 0.007). In contrast no differences in disease free survival were found for high NHERF1 expressing breast cancers which were either treated with endocrine therapy or no systemic therapy. Our data indicate that NHERF1 expressing breast cancers seem to have a greater risk to develop resistance to endocrine therapy. However, based on previous findings of NHERF1 functioning in PI3K signalling from basic research, these tumors might be appropriate candidates for a targeted therapy of the PI3K/Akt pathway.
authors.affiliation: Department of Obstetrics and Gynecology, J. W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. t.karn@em.uni-frankfurt.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Karn
authors.forename: Eugen
authors.initials: E
authors.lastname: Ruckhäberle
authors.forename: Lars
authors.initials: L
authors.lastname: Hanker
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christine
authors.initials: C
authors.lastname: Solbach
authors.forename: Regine
authors.initials: R
authors.lastname: Gätje
authors.forename: Mathias
authors.initials: M
authors.lastname: Gehrmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Holtrich
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Achim
authors.initials: A
authors.lastname: Rody
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor