title: Intrinsic breast cancer subtypes defined by estrogen receptor signalling-prognostic relevance of progesterone receptor loss.
abstract: The majority of luminal type breast carcinomas are slowly growing tumors with an overall favorable prognosis. However, a proportion of cases (luminal B tumors) are characterized by coactivation of growth factor receptors or non-canonical ER signaling and a poorer clinical outcome. The aim of our study was to evaluate whether the expression of proteins that are part of the ER signaling network may be used to distinguish low-risk from high-risk luminal tumors. Unsupervised hierarchical clustering of a set of proteins either involved in estrogen receptor signaling or associated with resistance to endocrine therapy was performed in a series of 443 postmenopausal breast carcinomas. Using this approach, we were able to reproduce the established classification with two distinct groups of luminal (estrogen receptor positive) tumors, one group of HER2-associated tumors and a group of triple-negative tumors. However, neither proliferation nor the expression of one or more of the ER-co-factors or resistance-associated factors, but PR-expression was identified as the most important stratifier distinguishing between the two luminal groups. In fact, not only the four identified clusters were shown to be significantly associated with patient outcome, PR-expression alone or in combination with Ki-67-stains stratified ER-positive tumors into a low-risk and a high-risk group. Our data indicate that defining luminal B tumors by the presence of high-risk criteria (loss of PR-expression or increased proliferation) provides a robust and highly significant stratification of ER-positive breast carcinomas into luminal A and B.
authors.affiliation: Institute of Pathology, Heidelberg University, Heidelberg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Braun
authors.forename: Friederike
authors.initials: F
authors.lastname: Mietzsch
authors.forename: Petra
authors.initials: P
authors.lastname: Seibold
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Hans
authors.initials: H
authors.lastname: Peter Sinn
authors.forename: Sebastian
authors.initials: S
authors.lastname: Aulmann
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D002277:Carcinoma / Q000737:chemistry* / Q000145:classification / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D016000:Cluster Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry* / Q000145:classification / Q000401:mortality / Q000473:pathology; D016017:Odds Ratio; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry* / Q000145:classification / Q000401:mortality / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human