Browsing by Subject "Breast Neoplasms"
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Item Analysis of Neurocognitive Elements of Attention Following Chemotherapy Treatment(2013-01-16) Grosch, Maria Catherine; Cullum, Colin Munro, Ph.D., ABPP-CNBreast cancer affects approximately 123 out of 100,000 women per year in the United States, with 207,090 new cases estimated each year (Altekruse et al., 2010). Adjuvant chemotherapy has become a staple of care to improve long-term outcomes for several types of breast cancers (de Boer, Taskila, Ojajärvi, van Dijk, & Verbeek, 2009). Because of advances in treatment, the overall 5-year survival rate for breast cancer patients is now estimated at 89% (Altekruse et al., 2010). With increased survival comes a greater concern for issues related to quality of life, including cognitive function. Unfortunately, cancer treatments may result in cognitive changes or impairment, with deficits ranging from minor to debilitating (Argyriou, Assimakopoulos, Iconomou, Giannakopoulou, & Kalofonos, 2011). The phenomenon of cognitive dysfunction following cancer treatment is often called “chemo-brain” by patients and in the media. Despite an increase in the number of published studies in recent years, many aspects of chemotherapy-related cognitive dysfunction remain poorly understood. The pattern of cognitive impairment and neurological damage (as seen on neuroimaging) is reflective of disruption of frontal subcortical networks (Meyers, 2008). Because attention and related constructs are of central importance in this so-called “subcortical profile,” it is important to have a thorough understanding of how these domains are impacted by chemotherapy. However, available literature is difficult to interpret, in part because of various methodological factors, including the use of singular or otherwise limited neuropsychological tests, inconsistent use of tests across studies, and variability in the conceptualization of domains believed to be affected by chemotherapy (such as attention and related constructs). Thus, conclusions regarding attentional impairment in women treated for breast cancer are limited, and its role in the clinical syndrome known as chemo-brain remains poorly understood.Item Characterization of the Role of the PP2A-AB Gene, a Putative Tumor Suppressor, in Cell Growth and Tumorigenesis(2005-05-11) Esplin, Edward D.; Mumby, MarcThe PP2A-Aᠧene (PPP2R1B) encodes the ᠩsoform of the A subunit of serine/threonine protein phosphatase 2A. Mutations in PP2A-Aᠨave been identified in a wide variety of human cancers. The important role of protein phosphatase 2A in down regulating cell growth suggests these mutations may contribute to cancer susceptibility and tumorigenesis by compromising the function of PP2A-Aᠡnd that PP2A-Aᠭay act as a tumor suppressor. Screening of cancer patient DNAs revealed an association between a germline alteration of the PP2A-A and breast carcinoma and identified alterations of PP2A-Aᠩn lung carcinoma and ALL patient genomic DNAs. The biochemical consequences of these PP2A-Aᠭutations on PP2A function were investigated by in vitro and in vivo coimmunoprecipitations between the PP2A-Aᠳubunit and the B and C subunits of PP2A. These studies showed mutations in PP2A-Aᠣonfer a loss of function by reducing its ability to bind the B and C subunits, destabilizing the PP2A-Aᠣontaining PP2A complex. The affect of the PP2A-Aᠧene on cell growth was analyzed by transfecting the PP2A-Aᠧene into cancer cell line deficient for wild type PP2A-Aᠡnd deriving stable cell lines. The PP2A-Aᠧene appeared to confer a relative disadvantage to transfected cells, resulting in a lower fraction of derived stable lines compared to controls. These cell lines were tested for proliferation and colony formation in soft agar. No significant difference was observed in the growth rate of PP2A-Aᠣell lines compared to controls. One of the PP2A-Aᠳtable cell lines demonstrated dramatic suppression of colony formation in soft agar, but this was not confirmed in any additional PP2A-Aᠳtable cell lines, leaving this finding inconclusive. The stable cell lines were also analyzed by Western blotting for changes in the Wnt signaling cascade. Cell lines expressing exogenous PP2A-Aᠡre found to have lower levels of ᭣atenin compared to control cell lines. This suggests that the PP2A-Aᠧene is involved in regulating the Wnt signaling pathway, which is shown to be involved in cell growth control and is similarly affected by known tumor suppressor genes.Item Cooperative Invasion Between Tumor Cell Subpopulations(2013-01-17) Prechtl, Amanda Miya; Pearson, Gray W., Ph.D.Breast cancer is responsible for over 40,000 deaths each year in the United States. The majority of these deaths are not attributable to the primary breast tumor, but to metastases in vital organs. Tumor cell invasion is an early step in the metastatic cascade which can occur collectively by multiple cells cooperatively invading into the surrounding stroma. Primary patient breast tumors and patient-derived breast cancer cells can collectively invade yet how cells collectively invade is still largely unknown. It is well known that tumors contain heterogenous populations of cells yet traditional metastasis models focus on the ability of a rare population of neoplastic cells to autonomously invade past the basement membrane surrounding the tumor, intravasate into blood vessels and disseminate throughout the body to colonize foreign tissues. We hypothesized that there is a stable subpopulation of tumor cells that is capable of initiating the invasion of another population. Using organotypic culture models, which provide a three dimensional environment that models stromal conditions, and real-time imaging, a technique in which cell behavior can be imaged in real time at a single cell resolution, we determined that breast cancer cell lines can contain populations of cells with differential invasive potential. Furthermore, we concluded that one population of invasvie cells is sufficient to induce the invasion of other noninvasvie cells. This suggests a new mechanism for breast cancer metastasis, in which subpopulations of cells can cooperate with each other as opposed to competing against each other, to invade and potentially metastasize. Future studies will focus on determining the requirements for the leader cells to induce invasion and the follower cells to migrate behind the leader cells, with the eventual goal of targeting specific tumor populations for diagnostic and therapeutic treatment.Item KU70 Binding Protein 5 (KUB5), A Novel Factor in DNA Double Strand Break Repair and Radio-Resistance in Human Breast Cancer(2011-02-01T19:37:12Z) Rommel, Amy Ann; Boothman, David A.DNA double strand breaks (DSBs) are considered both mutagenic and carcinogenic if left un-repaired resulting in genomic instability and ultimately cancer. There are two main pathways for DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). Defects in DSB repair have already been associated with breast cancer formation and increased breast cancer risk. Breast cancer susceptibility genes, BRCA1 and BRCA2 are largely thought to be involved with HR while LIG4, XRCC4, and Ku70 are linked to NHEJ. Deficiencies in any one of these genes can predispose individuals to breast cancer. In addition to predisposition to breast cancer, altered DNA repair processes can influence chemo- and radiotherapy efficacy by creating resistance to therapy. To study NHEJ further, our laboratory has identified a novel Ku70 binding protein #5 (KUB5) by a yeast two-hybrid screen using Ku70 as bait. Loss of RTT103, a putative yeast homolog of KUB5, resulted in increased sensitivity to IR, similar to that observed in hdf1-deletion yeast, the yeast homolog of Ku70. Results also show that RTT103-deletion yeast are deficient in repairing blunt and non-compatible DNA ends and re-expression of hKub5 can correct the IR-sensitivity and DNA repair deficiency of these deficient yeast demonstrating a strong functional model for human KUB5 function in yeast. Analyses of breast cancer cell lines for their KUB5 protein expression yielded a strong correlation between KUB5 protein level and sensitivity to DNA damage. These data strongly suggests that KUB5 is a novel repair factor involved in NHEJ and endogenous over-expression of KUB5 plays a role in chemotherapeutic and/or radio-therapeutic resistance via increasing the capacity to facilitate NHEJ repair of DSBs in breast cancer cells.Item Somatic Stem Cell Populations and Studies on the Functional Role and Regulation of ABCG2(2005-12-20) Tunison, Mary Katherine; Garry, DanielATP binding cassette transporters use ATP to transport substances such as sterols, peptides, drugs and other toxins across membranes. Abcg2 is a member of the G family of transporters that was identified in breast cancer cells due to its ability to efflux chemotherapeutic drugs. Abcg2 can also efflux Hoechst 33342, resulting in a side population phenotype when stained cells are sorted by FACS. Recent studies have suggested that Abcg2 may be a marker for stem and progenitor cells. This paper presents experiments that were undertaken to further evaluate the functional role and regulation of Abcg2. Preliminary data obtained from a microarray performed on main and side population cells indicated that side population cells were enriched for genes that are important in cytoprotection and cell cycle control. To confirm this observation, cell cycle analysis was performed on C2C12 myoblasts transfected with an Abcg2 overexpressing plasmid. Those cells that overexpressed Abcg2 and consequently effluxed Hoechst 33342 dye were arrested in G0/G1 phase of the cell cycle, consistent with the microarray results. To determine whether Abcg2 played a cytoprotective role I attempted to measure the viability of main population versus side population cells when exposed to the oxidative compound menadione. These experiments were inconclusive, most likely due to limitations of the cell line used. To assess the regulation of Abcg2 I examined evolutionary conservation between the upstream regions of mouse and human Abcg2. Conserved regions were identified up to 11kb upstream of the mouse gene. In these regions, putative binding sites were discovered for transcription factors that are involved in stem and progenitor cell regulation. Present studies support that Abcg2 is a marker for stem and progenitor cells. Future studies will uncover additional functional roles of the transporter.