title: Claudin-Low Breast Cancer; Clinical & Pathological Characteristics.
abstract: Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.|Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kay
authors.initials: K
authors.lastname: Dias
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Dvorkin-Gheva
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Hassell
authors.affiliation: Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Pond
authors.affiliation: Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
authors.affiliation: Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Tim
authors.initials: T
authors.lastname: Whelan
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.|Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Bane
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D010634:Phenobarbital / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D010634:Phenobarbital