A pathway-based classification of human breast cancer

Abstract

The hallmark of human cancer is heterogeneity, reflecting the complexity and variability of the vast array of somatic mutations acquired during oncogenesis. An ability to dissect this heterogeneity, to identify subgroups that represent common mechanisms of disease, will be critical to understanding the complexities of genetic alterations and to provide a framework to develop rational therapeutic strategies. Here, we describe a classification scheme for human breast cancer making use of patterns of pathway activity to build on previous subtype characterizations using intrinsic gene expression signatures, to provide a functional interpretation of the gene expression data that can be linked to therapeutic options. We show that the identified subgroups provide a robust mechanism for classifying independent samples, identifying tumors that share patterns of pathway activity and exhibit similar clinical and biological properties, including distinct patterns of chromosomal alterations that were not evident in the heterogeneous total population of tumors. We propose that this classification scheme provides a basis for understanding the complex mechanisms of oncogenesis that give rise to these tumors and to identify rational opportunities for combination therapies.

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…Classification of cancers has always posed a major challenge to scientists. The major categories currently include luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 (HER2)-positive [3–6] (Table 1). Recently, the use of gene expression microarrays has shed insight into the classification of various breast cancer subtypes, and these studies have demonstrated important overlap among subtypes since tumors demonstrate a high degree of molecular and genetic heterogeneity [3].…”

“…Recently, a signal transduction pathway-based scheme for classifying breast cancer has been developed [3]. Each subtype demonstrates specific alterations at the genomic level.…”

“…This heterogeneity may be due to the high numbers of somatic mutational events during cancer progression [3]. In order to develop novel therapeutic strategies, the heterogeneity must be understood, and cellular subtypes must be characterized [3].…”

“…This heterogeneity may be due to the high numbers of somatic mutational events during cancer progression [3]. In order to develop novel therapeutic strategies, the heterogeneity must be understood, and cellular subtypes must be characterized [3]. Each element of heterogeneity may represent a mechanism of oncogenesis that can be targeted by pharmacological therapy [3].…”

“…In order to develop novel therapeutic strategies, the heterogeneity must be understood, and cellular subtypes must be characterized [3]. Each element of heterogeneity may represent a mechanism of oncogenesis that can be targeted by pharmacological therapy [3]. With the discovery that cancers are more heterogeneous than once believed, personalized therapy for breast cancer may finds its way into the clinic.…”