Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential

Abstract

Human cancers result from a complex series of genetic alterations, resulting in heterogeneous disease states. Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity. Mouse models of cancer have generally been used to reduce this complexity and focus on the role of single genes. Nevertheless, our analysis of tumors arising in the MMTV-Myc model of mammary carcinogenesis reveals substantial heterogeneity, seen in both histological and expression phenotypes. One contribution to this heterogeneity is the substantial frequency of activating Ras mutations. Additionally, we show that these Myc-induced mammary tumors exhibit even greater heterogeneity, revealed by distinct histological subtypes as well as distinct patterns of gene expression, than many other mouse models of tumorigenesis. Two of the major histological subtypes are characterized by differential patterns of cellular signaling pathways, including ␤-catenin and Stat3 activities. We also demonstrate that one of the MMTV-Myc mammary tumor subgroups exhibits metastatic capacity and that the signature derived from the subgroup can predict metastatic potential of human breast cancer. Together, these data reveal that a combination of histological and genomic analyses can uncover substantial heterogeneity in mammary tumor formation and therefore highlight aspects of tumor phenotype not evident in the population as a whole.breast ͉ cancer ͉ genomics ͉ mouse

Prediction and Genetic Demonstration of a Role for Activator E2Fs in Myc-Induced Tumors

“…When Myc tumors were examined with this pathway signature technique, it was seen that there were a number of distinct histological classes of Myc-induced tumors that had characteristic gene expression patterns (4). Moreover, these various classes of Myc tumors, including papillary, microacinar, and EMT/ squamous were associated with unique patterns of signaling pathway activation.…”

“…This approach is built upon established statistical methods (1)(2)(3). Subsequently, the approach has been used to characterize human tumors, mouse mammary development, and recently to characterize the heterogeneity present within Mycinduced tumors (2,4,5). This method uses controlled training data for given pathways to develop a signature that is then applied to tumor gene expression data, enabling the prediction of probability of activation of various signaling pathways.…”

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing

“…Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity 9 . However, intratumoral genetic heterogeneity during gastric tumour progression has not been comprehensively investigated so far.…”

Use of Gene Expression and Pathway Signatures to Characterize the Complexity of Human Melanoma

“…For instance, breast cancer is a collection of diseases, each with distinct underlying molecular mechanisms and clinical characteristics. [1][2][3] The importance of dissecting the heterogeneity is illustrated with the example of trastuzumab (Herceptin), an important drug for the treatment of breast cancer, but only in the few patients who are Her2 positive. 4 This challenge is further compounded by the evident complexity of most cancers, involving multiple mutations and alterations that generate the cancer phenotype and, thus, requiring therapeutic strategies that can match the complexity with equally complex combination regimens.…”