Abstract Genomic profiling studies have demonstrated that a number of potentially targetable pathways are capable of contributing to breast cancer, including the fibroblast growth factor receptor (FGFR) pathway. Our studies focus on understanding the mechanisms through which FGFR1 activation in tumor cells leads to pro-tumorigenic changes in the microenvironment. Specifically, using an in an in vivo model of fibroblast growth factor receptor 1 (FGFR1)-induced mammary tumorigenesis, we have found that following FGFR1 activation in mammary epithelial cells, macrophages are recruited to the hyperplastic regions where they are required for angiogenesis and epithelial cell proliferation. To identify the factors that contribute to the pro-tumorigenic microenvironment, we have developed two- and three-dimensional co-culture in vitro models to mimic what is observed in vivo. Using these in vitro models, we have identified that soluble factors derived from FGFR1-activated epithelial cells lead to the upregulation of target genes in macrophages that promote tumor formation, invasion, and migration. Findings from the in vitro studies are further assessed using a mouse mammary tumor model utilizing orthotopic transplants into immunocompetent mice. These model systems will help us identify novel regulators of mammary tumorigenesis and provide new insight into the mechanisms by which macrophages promote tumor formation. Citation Format: Nicholas J. Brady, Mariya Farooqui, Laura Bohrer, Kaylee Schwertfeger. Contribution of macrophages to FGFR-dependent breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A098.
In India, obesity is an emerging health problem, along with its co morbidities. This is due to change in life style and dietary patterns of people in developing world. In India, there is rapid rise in number of deaths due to CVD and its prevalence in society is at an alarming rise. Around half of these deaths are of the people in there productive years leading to loss of productive workforce. This has occurred not only due to reduction in physical activity but also due to increased intake of saturated fats and decreased intake of staple foods. There is a rapid increase in cholesterol, triglycerides, and LDL levels while HDL levels are low. This can be curbed at an early stage by changes in lifestyle and diet. Though various diets have been advised and are being used in western individuals but it is a less looked upon topic in Indians, so in this article we try to look upon physical activity guidelines and dietary patterns advised for Indian population.
Abstract EGFR (Epidermal Growth Factor Receptor) is a major target for the treatment of Non-Small Cell Lung Cancer (NSCLC), but patients lacking EGFR mutation are insensitive to EGFR inhibition. Patients with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs), but eventually develop acquired resistance as a result of secondary mutations in the EGFR tyrosine kinase domain. Upregulation of Signal Transducer and Activator of Transcription (STAT3), a key oncogenic molecule in NSCLC that is downstream of EGFR signaling, contributes to intrinsic and acquired resistance to EGFR TKIs. In the clinic, agents targeting STAT3 have not been satisfactory to date. To address the limitations of available STAT3 inhibitors, we are currently testing a cyclic oligonucleotide molecule with a novel mechanism that acts as a STAT3 “decoy” (Cyclic STAT3 decoy, CS3D). CS3D mimics the DNA consensus sequence in the promoter region of STAT3-responsive genes, causing the binding of STAT3 dimers and preventing transcriptional regulation of STAT3-target genes. The effects of CS3D are compared to mutant cyclic STAT3 decoy (CS3M), which differs from CS3D by one base-pair. We have tested the ability of CS3D to produce anti-tumor effects in NSCLC cells that are EGFR WT (201T) and in EGFR mutant cells that also carry the T790M resistant mutation (H1975). Initial in vitro studies showed that CS3D caused a 50% inhibition in cell proliferation in 201T and H1975 relative to CS3M using MTS assays. Flow cytometry studies also demonstrated that CS3D caused a 2-fold increase in the percent of apoptotic cells as compared to CS3M. CS3D also caused a 2-fold reduction in expression of STAT3-target genes c-Myc, Bcl-xL and IL-6. Compared to CS3M, CS3D inhibited colony formation by 70%. Using an in vivo mouse xenograft model of 201T and H1975, CS3D caused a 96.5% reduction in tumor growth in 201T (P<0.007) compared to CS3M, while an 81.7% inhibition was seen in H1975 (P<.0001). Utilizing IHC, analysis of residual tumors also illustrated that CS3D induced more caspase3 cleavage relative to CS3M. Additionally, western blot analysis showed 70% reduction in c-Myc protein level in response to CS3D. These results suggest CS3D can be effective as a single therapeutic agent. Combining CS3D with EGFR inhibitors such as afatinib in vitro significantly suppressed cell viability by 85.2% and 80% in 201T and H1975 respectively, as compared to single treatment (CS3D alone reduced cell viability by 53%, and 51.5%, and afatinib alone reduced viability by 31.4% and 34.03% in 201T and H1975, respectively). The combination of CS3D and afatinib warrants further testing in vivo. These data suggest that CS3D alone or in combination with EGFR tyrosine kinase inhibitors produces anti-tumor effects in NSCLC with intrinsic and acquired resistance to EGFR TKIs. Supported by funding to the Masonic Cancer Center from the Minnesota 5th Order of Eagles. Citation Format: Christian Njatcha, Mariya Farooqui, Jennifer R. Grandis, Jill M. Siegfried. Targeting the EGFR/STAT3 axis in NSCLC with resistance to EGFR tyrosine kinase inhibitors using an oligonucleotide-based decoy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4101. doi:10.1158/1538-7445.AM2017-4101
The epidermal growth factor (EGF) family of ligands has been implicated in promoting breast cancer initiation, growth and progression. The contributions of EGF family ligands and their receptors to breast cancer are complex, and the specific mechanisms through which different ligands regulate breast tumor initiation and growth are not well-defined. These studies focus on the EGF family member epiregulin (EREG) as a mediator of early stage breast tumorigenesis.EREG expression levels were assessed in both cell lines and human samples of ductal carcinoma in situ (DCIS) using quantitative RT-PCR, ELISA and immunohistochemistry. Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival. Experiments were performed using a combination of two-dimensional culture, three-dimensional culture and tumor growth in vivo.In comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity. Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival. Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents. Examination of EREG-induced signaling pathways demonstrated that EREG promoted survival of MCF10A cells through regulating expression of matrix metalloproteinase-1 (MMP-1). To determine the relevance of these findings in human tumors, samples of DCIS were analyzed for EREG and MMP-1 expression. EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples.Together, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer. Understanding these complex pathways could ultimately lead to the development of novel biomarkers of neoplastic progression and/or new therapeutic strategies for patients with early stage cancer.
