Intracellular Signaling and Trafficking in Cancer: Role of Rab5-GTPase in Migration and Invasion of Breast Cells

Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. Steroid hormones, such as estrogen, and growth factors, which include insulin growth factor I/II (IGF-1/IGF-2) therapy has been associated with most if not all of the features of metastasis. It has been determined that IGF-1 increases cell survival of cancer cells and potentiate the effect of E2 and other ligand growth factors on breast cancer cells. However not much information is available that comprehensively expounds on the roles of insulin growth factor receptor (IGFR) and Rab GTPases may play in breast cancer. The latter, Rab GTPases, are small signaling molecules and critical in the regulation of many cellular processes including cell migration, growth via the endocytic pathway. This research involves the role of Rab GTPases, specifically Rab5 and its guanine exchange factors (GEFs), in the promotion of cancer cell migration and invasion. Two important questions abound: Are IGFR stimulation and downstream effect involved the endocytic pathway in carcinogenesis? What role does Rab5 play in cell migration and invasion of cancer cells? The hypothesis is that growth factor signaling is dependent on Rab5 activity in mediating the aggressiveness of cancer cells. The goal is to demonstrate that IGF-1 signaling is dependent on Rab5 function in breast cancer progression. Here, the results thus far, have shown that while activation of Rab5 may mediate increased cell proliferation, migration and invasion in breast cancer cells, the Rab5 GEF, RIN1 interacts with the IGFR thereby facilitating migration and invasion activities in breast cells. Furthermore, endocytosis of the IGFR in breast cancer cells seems to be caveolin dependent as the data has shown. This taken together, the data shows that IGF-1 signaling in breast cancer cells relies on IGF-1R phosphorylation, caveolae internalization and sequestration to the early endosome RIN1 function and Rab5 activation.

Exposure to endocrine disrupting compounds and reproductive toxicity in women

The overall objective of the research presented in this dissertation was to assess exposure to endocrine disrupting chemicals (EDCs), polychlorinated biphenyls (PCBs), phthalates, and bisphenol A (BPA) in the general population and evaluate their associations with adverse reproductive health effects, including cancers, in women. Given the proven contribution of unopposed estrogens to the risk for endometrial neoplasia or breast cancer, renewed health concerns have aroused about estrogen mimicking EDCs found in food, personal care products or as environmental contaminants. Our meta-analysis showed that exposure to estrogen mimicking PCBs increased summary risk of breast cancer and endometriosis. We further evaluated the relationship between endometriosis and breast cancer, and EDCs using a bioinformatics method. Our bioinformatics approach was able to identify genes with the potential to be involved in interaction with PCB, phthalates and BPA that may be important to the development of breast cancer and endometriosis. Therefore, we hypothesized that exposure to EDCs such as PCBs, phthalates, and BPA, results in adverse reproductive health effects in women. Using subject data and biomarkers available from the Center for Disease Controls National Health and Nutrition Examination Survey database we conducted a cross-sectional study of EDCs in relation to self-reported history of endometriosis, uterine leiomyomas, breast cancer, cervical cancer, ovarian cancer, and uterine cancer. Significantly higher body burdens of PCBs were found in women diagnosed with breast cancer, ovarian cancer, and uterine cancer compared to women without cancer. PCB 138 was significantly associated with breast cancer, cervical cancer, and uterine cancer, while PCBs 74 and 118 were significantly associated with ovarian cancer. The sum of dioxin-like PCBs were significantly associated with ovarian cancer (OR of 2.02, 95% CI: 1.06-3.85) and the sum of non-dioxin-like PCBs were significantly associated with uterine cancer (OR of 1.12, 95%CI: 1.03-1.23). Significantly higher body burdens of PCBs were also found in women diagnosed with endometriosis and uterine leiomyomas. Documenting the exposure to EDCs among the general U.S. population, and identifying agents associated with reproductive toxicity have the potential to fill research gaps and facilitate our understanding of the complex role environmental chemicals play in producing toxicity in reproductive organs.^

Exposure to Endocrine Disrupting Compounds and Reproductive Toxicity in Women

The overall objective of the research presented in this dissertation was to assess exposure to endocrine disrupting chemicals (EDCs), polychlorinated biphenyls (PCBs), phthalates, and bisphenol A (BPA) in the general population and evaluate their associations with adverse reproductive health effects, including cancers, in women. Given the proven contribution of unopposed estrogens to the risk for endometrial neoplasia or breast cancer, renewed health concerns have aroused about estrogen mimicking EDCs found in food, personal care products or as environmental contaminants. Our meta-analysis showed that exposure to estrogen mimicking PCBs increased summary risk of breast cancer and endometriosis. We further evaluated the relationship between endometriosis and breast cancer, and EDCs using a bioinformatics method. Our bioinformatics approach was able to identify genes with the potential to be involved in interaction with PCB, phthalates and BPA that may be important to the development of breast cancer and endometriosis. Therefore, we hypothesized that exposure to EDCs such as PCBs, phthalates, and BPA, results in adverse reproductive health effects in women. Using subject data and biomarkers available from the Center for Disease Controls National Health and Nutrition Examination Survey database we conducted a cross-sectional study of EDCs in relation to self-reported history of endometriosis, uterine leiomyomas, breast cancer, cervical cancer, ovarian cancer, and uterine cancer. Significantly higher body burdens of PCBs were found in women diagnosed with breast cancer, ovarian cancer, and uterine cancer compared to women without cancer. PCB 138 was significantly associated with breast cancer, cervical cancer, and uterine cancer, while PCBs 74 and 118 were significantly associated with ovarian cancer. The sum of dioxin-like PCBs were significantly associated with ovarian cancer (OR of 2.02, 95% CI: 1.06-3.85) and the sum of non-dioxin-like PCBs were significantly associated with uterine cancer (OR of 1.12, 95%CI: 1.03-1.23). Significantly higher body burdens of PCBs were also found in women diagnosed with endometriosis and uterine leiomyomas. Documenting the exposure to EDCs among the general U.S. population, and identifying agents associated with reproductive toxicity have the potential to fill research gaps and facilitate our understanding of the complex role environmental chemicals play in producing toxicity in reproductive organs.

Intracellular signaling and trafficking in cancer: Role of Rab5-GTPases in migration and invasion of breast cancer cells

Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. Steroid hormones, such as estrogen, and growth factors, which include insulin growth factor I/II (IGF-1/IGF-2) therapy has been associated with most if not all of the features of metastasis. It has been determined that IGF-1 increases cell survival of cancer cells and potentiate the effect of E2 and other ligand growth factors on breast cancer cells. However not much information is available that comprehensively expounds on the roles of insulin growth factor receptor (IGFR) and Rab GTPases may play in breast cancer. The latter, Rab GTPases, are small signaling molecules and critical in the regulation of many cellular processes including cell migration, growth via the endocytic pathway. This research involves the role of Rab GTPases, specifically Rab5 and its guanine exchange factors (GEFs), in the promotion of cancer cell migration and invasion. Two important questions abound: Are IGFR stimulation and downstream effect involved the endocytic pathway in carcinogenesis? What role does Rab5 play in cell migration and invasion of cancer cells? The hypothesis is that growth factor signaling is dependent on Rab5 activity in mediating the aggressiveness of cancer cells. The goal is to demonstrate that IGF-1 signaling is dependent on Rab5 function in breast cancer progression. Here, the results thus far, have shown that while activation of Rab5 may mediate increased cell proliferation, migration and invasion in breast cancer cells, the Rab5 GEF, RIN1 interacts with the IGFR thereby facilitating migration and invasion activities in breast cells. Furthermore, endocytosis of the IGFR in breast cancer cells seems to be caveolin dependent as the data has shown. This taken together, the data shows that IGF-1 signaling in breast cancer cells relies on IGF-1R phosphorylation, caveolae internalization and sequestration to the early endosome RIN1 function and Rab5 activation.^