Intrinsic breast cancer subtypes defined by estrogen receptor signalling-prognostic relevance of progesterone receptor loss.

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.

Transitions between flat epithelial atypia and low-grade ductal carcinoma in situ of the breast.

Flat epithelial atypia (FEA) of the breast typically is a localized alteration involving only few, neighboring terminal ducto-lobular units. However, occasionally there are cases with extensive FEA and morphologic evidence of direct transitions between FEA and classical low-grade ductal carcinoma in situ (lg-DCIS). To investigate the relationship between FEA and DCIS in these cases, we microdissected multiple foci of the respective lesions in a series of 10 cases and performed comparative allelotyping using a panel of 14 loss of heterozygosity markers. In addition, phylogenetic tree models were calculated on the basis of mitochondrial DNA sequencing to visualize the clonal relationship of the different lesions. FEA and lg-DCIS shared the majority of chromosomal imbalances; loss of diverging alleles was not detected in any of the 10 cases. Mitochondrial DNA sequencing and phylogenetic tree clustering revealed direct transitions between FEA and lg-DCIS in all 10 cases. However, in 3 patients, additional foci of FEA were present, which were not directly related to the rest of the FEA and the lg-DCIS. Our data demonstrate the presence of direct transitions between FEA and lg-DCIS and support the interpretation of FEA as part of the low-grade pathway in the development of breast cancer.