The role of interstitial fluid flow on breast cancer progression

The majority of deaths associated with breast cancer result from the ability of the cancer cells to invade the surrounding environment and spread to distant sites. The tumor microenvironment includes a variety of biophysical forces whose effects are known to influence cancer invasion and progression. Interstitial fluid flow (IFF) is one such force that is present in normal breast tissue and elevated in tumors. The focus of this dissertation was to study the effects of IFF coupled with overexpression of the proto-oncogene HER2 on breast cancer progression. The combined roles IFF and HER2 play on invasion had never been studied, especially in the context of how they may together influence the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Using 3-dimensional cell culture-based assays, we demonstrated that IFF activates molecular mechanisms that are HER2-independent and leads to invasion of different stages of tumor development through the phosphoinositide-3-kinase (PI3K). This phenomenon was observed both in single cells and in breast cancer-like acini structures. We identified that in normal cells, IFF-induced PI3K activation was modulated by EGFR, a growth factor whose signaling is tightly controlled in normal tissue. In invasive cancer cells, IFF-induced PI3K activation was modulated by the metastasis-associated chemokine receptor CXCR4. Furthermore, we observed that IFF-induced CXCR4 signaling only occurred in cells that have undergone EMT. Finally, using an approach to isolate IFF responsive cells, we observed that HER2 positive epithelial cells that invaded in response to IFF developed mesenchymal-like characteristics and displayed a lower sensitivity to HER2 drug treatment. Taken together, our findings suggest for the first time the role IFF plays on cellular transformation and drug resistance. In addition, they reveal IFF as a major contributor to breast cancer progression and highlight its implications on breast cancer therapy.Ph.D., Biomedical Engineering -- Drexel University, 201

Proteomic Profiling of Infiltrating Ductal Carcinoma Reveals Increased Cellular Interactions with Tissue Microenvironment

Progression of invasive carcinoma involves the deregulation of molecular signaling pathways that results in the acquisition of oncogenic phenotypes. Functional enrichment analysis allows for the identification of deregulated pathways from omics scale expression data. Given the importance of post-transcriptional regulatory mechanisms on protein expression and function, identification of deregulated pathways on the basis of protein expression data is likely to provide new insights. In this study, we have developed methods for label-based mass spectrometry in a large number of samples and applied these methods toward identification and quantification of protein expression in samples of infiltrating ductal carcinoma, benign breast growths, and normal adjacent tissue. We identified 265 proteins with differential expression patterns in infiltrating ductal carcinoma relative to benign growths or normal breast tissue. Analysis of the differentially expressed proteins indicated the deregulation of signaling pathways related to proliferation, invasion and metastasis, and immune response. Our approach provides complementary information to gene expression microarray data and identifies a number of deregulated molecular signaling pathways indicative of breast cancer progression that may enable more accurate, biologically relevant diagnoses and provide a stepping stone to personalized treatment

Proteomic Profiling of Infiltrating Ductal Carcinoma Reveals Increased Cellular Interactions with Tissue Microenvironment

Progression of invasive carcinoma involves the deregulation of molecular signaling pathways that results in the acquisition of oncogenic phenotypes. Functional enrichment analysis allows for the identification of deregulated pathways from omics scale expression data. Given the importance of post-transcriptional regulatory mechanisms on protein expression and function, identification of deregulated pathways on the basis of protein expression data is likely to provide new insights. In this study, we have developed methods for label-based mass spectrometry in a large number of samples and applied these methods toward identification and quantification of protein expression in samples of infiltrating ductal carcinoma, benign breast growths, and normal adjacent tissue. We identified 265 proteins with differential expression patterns in infiltrating ductal carcinoma relative to benign growths or normal breast tissue. Analysis of the differentially expressed proteins indicated the deregulation of signaling pathways related to proliferation, invasion and metastasis, and immune response. Our approach provides complementary information to gene expression microarray data and identifies a number of deregulated molecular signaling pathways indicative of breast cancer progression that may enable more accurate, biologically relevant diagnoses and provide a stepping stone to personalized treatment

Proteomic Profiling of Infiltrating Ductal Carcinoma Reveals Increased Cellular Interactions with Tissue Microenvironment

Progression of invasive carcinoma involves the deregulation of molecular signaling pathways that results in the acquisition of oncogenic phenotypes. Functional enrichment analysis allows for the identification of deregulated pathways from omics scale expression data. Given the importance of post-transcriptional regulatory mechanisms on protein expression and function, identification of deregulated pathways on the basis of protein expression data is likely to provide new insights. In this study, we have developed methods for label-based mass spectrometry in a large number of samples and applied these methods toward identification and quantification of protein expression in samples of infiltrating ductal carcinoma, benign breast growths, and normal adjacent tissue. We identified 265 proteins with differential expression patterns in infiltrating ductal carcinoma relative to benign growths or normal breast tissue. Analysis of the differentially expressed proteins indicated the deregulation of signaling pathways related to proliferation, invasion and metastasis, and immune response. Our approach provides complementary information to gene expression microarray data and identifies a number of deregulated molecular signaling pathways indicative of breast cancer progression that may enable more accurate, biologically relevant diagnoses and provide a stepping stone to personalized treatment

Proteomic Profiling of Infiltrating Ductal Carcinoma Reveals Increased Cellular Interactions with Tissue Microenvironment

Progression of invasive carcinoma involves the deregulation of molecular signaling pathways that results in the acquisition of oncogenic phenotypes. Functional enrichment analysis allows for the identification of deregulated pathways from omics scale expression data. Given the importance of post-transcriptional regulatory mechanisms on protein expression and function, identification of deregulated pathways on the basis of protein expression data is likely to provide new insights. In this study, we have developed methods for label-based mass spectrometry in a large number of samples and applied these methods toward identification and quantification of protein expression in samples of infiltrating ductal carcinoma, benign breast growths, and normal adjacent tissue. We identified 265 proteins with differential expression patterns in infiltrating ductal carcinoma relative to benign growths or normal breast tissue. Analysis of the differentially expressed proteins indicated the deregulation of signaling pathways related to proliferation, invasion and metastasis, and immune response. Our approach provides complementary information to gene expression microarray data and identifies a number of deregulated molecular signaling pathways indicative of breast cancer progression that may enable more accurate, biologically relevant diagnoses and provide a stepping stone to personalized treatment