We developed stromal-and epithelial-specific cre-transgenic mice to directly visualize epithelial-mesenchymal transition (EMT) during cancer progression in vivo. Using three different oncogene-driven mouse mammary tumor models and cell-fate mapping strategies, we show in vivo evidence for the existence of EMT in breast cancer and show that myc can specifically elicit this process. Hierarchical cluster analysis of genomewide loss of heterozygosity reveals that the incidence of EMT in invasive human breast carcinomas is rare, but when it occurs it is associated with the amplification of MYC. These data provide the first direct evidence for EMT in breast cancer and suggest that its development is favored by myc-initiated events. [Cancer Res 2008;68(3):937-45]

The synaptic localization, clustering, and immobilization of neurotransmitter receptors and ion channels play important roles in synapse formation and synaptic transmission. Although several proteins have been identified that interact with AMPA receptors and that may regulate their synaptic targeting, little is known about the interaction of AMPA receptors with the cytoskeleton. In studies examining the interaction of the AMPA receptor GluR1 subunit with neuronal proteins, we determined that GluR1 interacts with the 4.1G and 4.1N proteins, homologs of the erythrocyte membrane cytoskeletal protein 4.1. Using the yeast twohybrid system and a heterologous cell system, we demonstrated that both 4.1G and 4.1N bind to a membrane proximal region of the GluR1 C terminus, and that a region within the C-terminal domain of 4.1G or 4.1N is sufficient to mediate the interaction. We also found that 4.1N can associate with GluR1 in vivo and colocalizes with AMPA receptors at excitatory synapses. Disruption of the interaction of GluR1 with 4.1N or disruption of actin filaments decreased the surface expression of GluR1 in heterologous cells. Moreover, disruption of actin filaments in cultured cortical neurons dramatically reduced the level of surface AMPA receptors. These results suggest that protein 4.1N may link AMPA receptors to the actin cytoskeleton.

Recent breast cancer studies have highlighted the importance of interactions between cancer epithelium and tumor stroma. Recently, the focus of solid tumor investigations has shifted from mutations in carcinomatous epithelium to disturbances of tissue organization in cancer. The genetic basis of this microenvironment, however, remains to be clarified. To begin to resolve this problem, a total genome loss of heterozygosity (LOH) scan was done on epithelial and stromal DNA from 134 sporadic invasive breast carcinomas. In addition to detecting more frequent LOH at three loci in stroma than in epithelium, we found strong evidence that LOH frequencies were significantly elevated in specific regions of each chromosome. We detected 57 markers, which were preferentially lost either in stroma (n ‫؍‬ 38) or epithelium (n ‫؍‬ 19), relative to the background LOH frequencies on their respective chromosomes. This multiplicity of stromal cell LOH, and hence loss of genetic material, provides a possible mechanism for interpatient variation in host-stromal response to invading adenocarcinoma cells. This is consistent with a model in which initial, random LOH occurs equally among epithelium and stroma, but subsequent clonal selection is driven by factors, which appear to be distinctly different between malignant epithelial and surrounding stromal cells. Genetic alterations in stroma did not mimic those in epithelium, but they could play a different and parallel role in carcinogenesis and tumor progression, probably by modifying some features specific to breast cancer.

A HIGH DEGREE OF VARIABILITY IS observed in both biological behavior and clinical outcome in sporadic breast cancer, and this interpatient diversity in breast cancer biology and behavior may confound clinical management based on averages. Breast conserving surgery has become the standard of care for early stage breast cancer. In a recently published study, 2929 patients with early stage breast cancer were examined for the relative impact of the patient, the surgeon, hospital factors, or all 3 on surgical treatment outcome variation in patients with breast cancer. The study by Gort et al 1 showed that 91.2% of the total variance was attributable to the patient level (there was large interpatient variability). These data suggested that interpatient variation accounts for the high degree of clinical variability. Indeed, the demand for personalized medicine illustrates the medical community's and public's recognition of interpatient variability. It has been recognized for decades that identical chemotherapeutic regimens for similar stage and grade in patients with, for example, breast cancer (or virtually any malignancy) respond differently. Context That genomic alterations occur in both the epithelium and stroma of sporadic breast cancers has been documented by several groups. However, whether these microenvironmental alterations relate to clinicopathological features is unknown.Objective To analyze the relationship between stromal genomic alterations and presenting clinicopathological features in sporadic breast cancer. Main Outcome Measures Association of the loss of heterozygosity/allelic imbalance, in both the stroma and epithelium, with presenting clinicopathological features, such as tumor grade, expression status of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2, clinical stage, and regional lymph node metastasis status. Associations were assessed in regression models and tested with Fisher exact test. Bonferroni correction was applied to P values, with significance set at PϽ.0022. Design, Setting, and Participants