Systems biology and genomics of breast cancer

Abstract

It is now accepted that breast cancer is not a single disease, but instead it is composed of a spectrum of tumor subtypes with distinct cellular origins, somatic changes, and etiologies. Gene expression profiling using DNA microarrays has contributed significantly to our understanding of the molecular heterogeneity of breast tumor formation, progression, and recurrence. For example, at least two clinical diagnostic assays exist (i.e., OncotypeDX RS and Mammaprint®) that are able to predict outcome in patients using patterns of gene expression and predetermined mathematical algorithms. In addition, a new molecular taxonomy based upon the inherent, or "intrinsic," biology of breast tumors has been developed; this taxonomy is called the "intrinsic subtypes of breast cancer," which now identifies five distinct tumor types and a normal breast-like group. Importantly, the intrinsic subtypes of breast cancer predict patient relapse, overall survival, and response to endocrine and chemotherapy regimens. Thus, most of the clinical behavior of a breast tumor is already written in its subtype profile. Here, we describe the discovery and basic biology of the intrinsic subtypes of breast cancer, and detail how this interacts with underlying genetic alternations, response to therapy, and the metastatic process.

Figure 1.

677 breast tumors analyzed using hierarchical clustering and the Intrinsic/UNC 1300 gene list. A single data set of 340 samples from UNC and 337 from the Netherlands Cancer Institute were combined using Distance Weighted Discrimination (Benito et al. 2004), and then clustered together to yield a large and homogenous data set containing over 470 different tumors with RFS and OS data. The clustering analysis identified the 5 major intrinsic subtypes of luminal A, luminal B, normal-like, basal-like, and HER2-enriched, and also identified the newest subtype in the center called the “claudin-low” group. The gene sets most definitive of each subtype are shown and are (A) HER2-amplicon gene set, (B) basal epithelial gene set, (C) luminal epithelial gene set containing ER, and (D) proliferation gene set. (E) Claudin-low gene set including E-cadherin and claudin 3, 4, and 7. (F) Kaplan-Meier plot for survival based upon disease-specific survival (DOD) for the six groups described here. Scale bar showing the expression levels of each gene relative to the median expression.

Figure 2.

Hierarchical clustering analysis of primary tumors and metastases taken from Weigelt et al. (2005) and reproduced with permission from AACR Publications © 2005. A hierarchical clustering analysis was performed using a 1300-gene intrinsic gene list from Hu et al. (2006). Genes were arranged in horizontal and samples in vertical. Sample names in red represent six primary tumor-distant metastasis pairs; those in light blue represent primary tumor-lymph node metastasis pairs; and those in pink represent local and distant metastasis samples from autopsy patients (which for patient A1 includes the primary).