Browsing by Subject "Breast--Cancer"
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Item Characterization of metastasis regulators in human breast cancer: implications for tumor suppressor PTEN and the Rho family of small GTPases(2005) Baugher, Paige Jennette; Dharmawardane, SuranganiCancer metastasis is a multi-faceted process requiring the disregualtion of numerous signaling pathways, including those associated with cell adhesion and motility. Recent data indicates strongly that growth at a primary tumor site and growth at a metastatic site differ by the expression and/or context-dependent function of the metastasis regulator, and that a wide variety of signaling pathways are affected. PTEN (phosphatase and tensin homologue deleted on chromosome ten) then becomes an attractive candidate for a metastasis suppressor, based on its ability to negatively regulate numerous pathways involved in cell survival, cell proliferation, and cell motility. Conversely, the Rho family of small GTPases have become attractive candidates as contributors to metastasis. Rho GTPases regulate numerous signaling pathways involved in cell survival, cell proliferation and cell motility, but they function to enhance these processes instead of inhibiting them. Data presented here demonstrates the ability of PTEN to negatively regulate motility in human metastatic breast cancer cells without causing the cells to undergo apoptosis. PTEN is localized in stimulated cells away from the leading edge, which displaces it from sites of active motility signaling and prevents it from inhibiting these processes. Furthermore, ectopic PTEN expression is shown to downregulate phosphoinositol (3,4,5) triphosphate (PIP3), expression. Therefore, PTEN could be acting as a metastasis suppressor in human breast cancer. Data presented here also demonstrate the ability of the Rac subfamily of Rho GTPases to enhance metastatic properties and contribute to metastasis. Increased Rac activity was shown to correlate with increased metastatic potential in a panel of metastatic human breast cancer cell variants. When activated Rac1 or Rac3 was expressed stably in the least metastatic variant, either isoform was found to enhance adhesion, migration, and invasion in vitro, as well as contribute to pulmonary metastasis in the nude mouse model of experimental metastasis. Conversely, when dominant negative Rac1 or Rac3 was expressed in the most metastatic variant, either isoform was found to decrease adhesion, migration, and invasion in vitro, as well as block pulmonary metastasis in vivo. Therefore, Rac1 and/or Rac3 are found to act as metastasis regulators by negatively regulating metastatic human breast cancer progression.Item Fatigue, self-efficacy for physical activity, physical activity, and quality of life in women with breast cancer(2001-12) Haas, Barbara Kay; Stuifbergen, Alexa, 1955-This descriptive correlational study was conducted to examine the direct and indirect influences of fatigue, self-efficacy for physical activity, and physical activity on quality of life (QOL) in women with breast cancer. Relationships among these variables were compared between women with breast cancer and a comparison group of women. A theoretical model, philosophically congruent with a health within illness perspective and generated by integrating selected concepts from Pender’s Health Promotion Model and Bandura’s Social Cognitive Theory, was used to guide the study. Instruments used to measure study concepts included the Piper Fatigue Scale to evaluate fatigue; a researcher developed Physical Activity Assessment Inventory to measure self-efficacy for physical activity; the Human Activity Profile to calculate physical activity; and the McGill QOL Questionnaire to assess QOL. Participants (n =128) included 73 women receiving either chemotherapy or hormonal therapy for any stage breast cancer and 55 women in a comparison group with no history of cancer. The participants were primarily Caucasian, educated, and married. Correlational analyses suggested moderately strong relationships among the research model variables (fatigue, self-efficacy for physical activity, physical activity, and QOL) for both groups of women. There was an inverse relationship between fatigue scores and the scores for self-efficacy for physical activity, physical activity, and QOL. There was a direct relationship among the scores for self-efficacy for physical activity, physical activity, and QOL. Women receiving treatment for breast cancer reported higher levels of fatigue and lower levels of self-efficacy for physical activity and physical activity than women in the comparison group did. There was no difference in QOL scores between the groups. Results from path analysis supported the research model, explaining 53% of the variance in QOL scores. Fatigue has direct and indirect influences on QOL that are partially mediated by self-efficacy for physical activity and physical activity. Self-efficacy for physical activity directly influences physical activity, which then directly influences QOL. This research provides knowledge to help guide nursing care of women receiving treatment for breast cancer. Continued research and refinement of the model is required to determine additional influences of QOL in women receiving treatment for breast cancer.Item Investigation of the molecular mechanisms of apoptosis induced by a novel vitamin E derivative ([alpha]-TEA) in human breast and ovarian cancer using cell culture(2005) Shun, Ming-chieh; Kline, Kimberly; Sanders, Bob G.Previous studies from our lab have shown that the vitamin E derivative, RRR-α-tocopheryl succinate (vitamin E succinate, VES) induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo DNA synthesis arrest, cellular differentiation, and apoptosis. Several studies have demonstrated VES to be a potent pro-apoptotic agent inducing apoptosis by restoring both transforming growth factor-β (TGF-β) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptosis. In an effort to develop a more clinically useful vitamin E-based chemotherapeutic agent, a non-hydrolyzable ether analog of RRR-α-tocopherol; namely, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (called RRR-α-tocopherol ether acetic acid analog; and abbreviated α-TEA) has been produced. Specific aim I studies investigated the individual effects of α-TEA and a naturally occurring from of vitamin E, δ-tocotrienol, as anticancer agents against breast cancer in vitro, and characterized signaling events involved in the pro-apoptotic and differentiation actions of α-TEA in human MDA-MB-435 and MCF-7 breast cancer cell lines. Data reported here showed that both α-TEA and δ-tocotrienol, like VES, induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no or lower levels of apoptosis in normal human mammary epithelial cells (HMECs) and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct α-TEA and δ-tocotrienol were identical to those previously reported for VES, that is α-TEA- and δ-tocotrienol-induced apoptosis involved sensitizing both cell lines to TGF-β and Fas apoptotic signaling, involving up-regulation of TGF-β receptor II protein expression and signaling apoptosis by TGF-β, and Fas converging on JNK signaling pathway. Specific aim II characterized the apoptotic effects of α-TEA on components of the Fas/CD95 apoptotic pathway in cisplatin-sensitive, A2780S, and cisplatin-resistant, A2780/cp70R human ovarian cancer cells. Both ovarian cancer cells were shown to undergo apoptosis in a dose-dependent manner following α-TEA treatment. α-TEA-induced apoptosis involved downregulation of Akt activation and c-FLIP and survivin expression. Data showed α-TEA to be an efficient inducer of cell death by decreasing constitutive active Akt in ovarian cancer cells. Downregulation of Flip and survivin expression were identified as key proapoptotic events regulated by Akt in α-TEA-induced apoptosis. Specific aim III studies showed α-TEA to induce MDA-MB-435 human breast cancer cells to undergo cellular differentiation. We use four markers to determine α-TEA induces differentiation including Oil red O staining of neutral lipids, downregulation of Her2/neu protein, upregulation of cytokeratin 18 and upregulation of p21. Studies showed α-TEA to induce human MDA-MB-435 cells to undergo cellular differentiation in a manner similar to, if not identical, to VES induced differentiation. Specific aim IV studies showed α-TEA to modulate ErbB family members and signaling. Studies showed α-TEA inhibited cell growth of both A2780S and A2780/CP70R cells and heregulin partially rescued both cell lines from α-TEA-induced apoptosis. α-TEA downregulated ErbB1, ErbB2, and ErbB3 message and protein levels, but not ErbB4, and reduced phosphorylated Akt and ERK1/2 in a time and dose dependent manner. Taken together, these findings demonstrated that α-TEA-induced apoptosis is by downregulation of c-FLIP and survivin through the activity of Akt and elimination of tumor cells through Fas-mediated apoptosis, and showed α-TEA to be a potent inducer of apoptosis in both human breast and ovarian cancer cells in culture.Item Mechanisms of proliferation inhibition and apoptosis induced by vitamin E compounds and cyclooxygenase inhibitors in human breast cancer cells(2004) Zhang, Shuo; Kline, Kimberly; Sanders, Bob G.RRR-a-tocopheryl succinate (VES) and a-TEA [2, 5, 7, 8 - tetramethyl - 2R-(4R, 8R-12-trimethyltridecyl)chroman-6-yloxyacetic acid], a nonhydrolyzable ether analog of VES, induce growth inhibition in various human breast cancer cells. Cyclooxygenase 2 (COX-2) is up-regulated in human breast tumor tissues and cell lines, and has been shown to be associated with the process of neoplastic transformation and inhibition of apoptosis. Aims of this study were to investigate the individual and combined effects of vitamin E compounds (especially, a-TEA) and COX-2 selective inhibitors (especially, celecoxib) in protection against breast cancer in vitro and in vivo, and to determine their cellular and molecular signaling mechanisms. Using an MDA-MB-435-FL-GFP human breast cancer xenograft model, a-TEA and celecoxib separately or in combination significantly reduced tumor volume in comparison to control. The combination of a-TEA + celecoxib (1,250 mg/kg diet) significantly inhibited tumor volume in comparison to single treatments. Mean numbers of microscopic lung and lymph node metastases in all treatment groups were significantly lower than control. Furthermore, the mean number of microscopic lung metastases in the a-TEA + celecoxib (1,250) group was significantly lower in comparison to separate treatments. Analyses of 5 micron tumor sections showed that all treatments, with the exception of celecoxib (500) alone, to significantly enhance apoptosis and significantly decrease cell proliferation. Similarly, in vitro studies using MDA-MB-435-FL-GFP cells showed a-TEA or celecoxib to induce apoptosis and DNA synthesis arrest. Combination of a-TEA + celecoxib synergistically enhanced apoptosis and additively enhanced DNA synthesis arrest. Celecoxib coordinately mediated aTEA’s anticancer effects by enhancing the c-Jun-N-terminal kinase (JNK) and cJun apoptotic signaling pathway, reducing cell proliferation, reducing cell cycle regulators (cyclin A and E, Proliferation Cell Nuclear Antigen), and suppressing cell migration putatively via alternating integrin-mediated cell adhesion signaling pathways. In conclusion, simultaneous targeting of breast cancer cells in vitro or in vivo with a-TEA and celecoxib separately and together inhibited cancer growth by inducing cell death by apoptosis, G0/G1 cell cycle blockage, inhibiting proliferation, and suppressing cell migration more effectively than targeting with each compound alone. These data show promise for combinations of a-TEA + celecoxib for breast cancer chemotherapyItem Membrane progestin receptor expression, signaling and function in reproductive somatic cells of female vertebrates(2008-05) Dressing, Gwen Ellen, 1980-; Thomas, P. (Peter)The goal of the current research was to examine the expression, signaling and function of the membrane progestin receptors (mPRs) in the ovarian follicular cells of the Atlantic croaker (Micropogonias undulatus) and in human breast cancer cells. Multiple studies have examined the role of mPRs in the germ cells of several vertebrate classes, yet few studies have examined the role of the mPRs in the somatic cells of reproductive tissues. Therefore this research examines the mechanism of mPR action and its function in somatic cells of female reproductive tissues. Results from studies on the expression, localization and signaling of the mPR[alpha] in co-cultures of granulosa and theca cells from the croaker suggest that the mPR[alpha] is localized to the plasma membrane of both cell types and that the mPR[alpha] is associated with and signals via pertussis toxin-sensitive inhibitory G proteins to decrease intracellular cAMP and activate ERK. In addition, exposure of follicular co-cultures to progestins that activate the mPR[alpha] results in a decrease in serum starvation-induced cell death which is not replicated by progestins which activate the nuclear progestin receptor (nPR), indicating mPR mediation. Similar studies in two immortalized human breast cancer cell lines, MDA-MB-468 and SKBR3, suggest that the mPR[alpha] is also present in the membranes of these cells and signals in human breast cancer cell lines via activation of a pertussis toxin-sensitive G protein to significantly decrease in intracellular cAMP and activate ERK. Progesterone exposure also decreased serum starvation-induced cell death in SKBR3 cells which are nPR positive and in MDA-MB-468 cells which are nPR negative. Synthetic progestins which activate the nPR but not the mPR were ineffective in inhibiting death in either cell type suggesting that the mPR is the mediator of this progestin action. mPR[alpha], mPR[beta] and mPR[gamma] expression analysis of paired normal and malignant breast tissue biopsies from thirteen women revealed that at least one mPR isoform was upregulated in the malignant tissue of 70% of the women. In addition the expression of mPR[gamma] was positively correlated with the expression of the nPR and CK19, a breast epithelial cell marker.Item Utilities of metastatic breast cancer patients treated with taxanes compared to utilities of oncology nurses(2001-08) Hauser, Robert Sean, 1972-; Koeller, JimUtility analyses are rapidly becoming a standard measure for many oncology studies. A recent publication in JCO reported utility scores obtained from 40 published studies and presented the results in a league table format (Earl et al. J Clin Oncl, 2000;18(18): 3302- 2217). The majority of the studies utilized healthcare professionals (nurses and physicians) as proxies for the patients with the disease state studied. The main objective of this study was to determine if there is a significant difference between utility scores obtained from metastatic breast cancer patients and oncology nurses. Using eight Markov modeled health states describing metastatic breast cancer; the standard gamble procedure was utilized to obtain utility scores from 45 patients and 57 oncology nurses. Utility values are measured on a scale between 0.0 and 1.0. Independent t-tests were used to test for differences between groups using an alpha level of 0.05. Significant differences (all p values <0.001) were found on all eight modeled health states. Patients reported a utility score of 0.84 (sd=0.11) compared to 0.71 (sd=0.22) reported by nurses on the “Partial Response (PR)” health state. Patients reported a utility score of 0.78 (sd=0.17) compared to 0.63 (sd=0.24) reported by nurses on the “PR with Severe Peripheral Edema” health state. Patients reported a utility score of 0.76 (sd=0.13) compared to 0.56 (sd=0.24) reported by nurses on the “PR with Severe Peripheral Neuropathy” health state. Patients reported a utility score of 0.73 (sd=0.16) compared to 0.59 (sd=0.22) reported by nurses on the “Before Second Line Treatment Begins” health state. Patients reported a utility score of 0.72 (sd=0.15) compared to 0.54 (sd=0.22) reported by nurses on the “Stable Disease” health state. Patients reported a utility score of 0.63 (sd=0.18) compared to 0.45 (sd=0.25) reported by nurses on the “Late Progressive Disease” health state. Patients reported a utility score of 0.40 (sd=0.26) compared to 0.19 (sd=0.21) reported by nurses on the “Terminal Disease” health state. Patients reported a utility score of 0.39 (sd=0.25) compared to 0.20 (sd=0.23) reported by nurses on the “Sepsis” health state. These results suggest that patients have a higher utility for health than nurses perceive the patients as having. Furthermore, these results may show that when performing cost-utility analysis, that a patient utility measure should be incorporated into the decision model rather than a proxy score obtained by a healthcare professional. Further studies should compare patients in other disease states with healthcare professionals to see if these results hold true for other disease states. These results also lead to the question of who’s utility values should we use for cost-utility analysis in oncology.