Matching Items (41)
Description
The p53 gene functions as a tumor suppressor that inhibits proliferation, regulates apoptosis, DNA repair, and normal cell cycle arrest. Mutation of the p53 gene is linked to be prevalent in 50% of all human cancers. In this paper, we are exploring triple negative breast cancer and the effects of simvastatin on tumor growth and survival. Simvastatin is a drug that is primarily used to treat high cholesterol and heart disease. Simvastatin is unique because it is able to inhibit protein prenylation through regulation of the mevalonate pathway. This makes it a potential targeted drug for therapy against p53 mutant cancer. The mechanism behind this is hypothesized to be correlated to aberrant activation of the Ras pathway. The Ras subfamily functions to transcriptionally regulate cell growth and survival, and will therefore allow for a tumor to thrive if the pathway is continually and abnormally activated. The Ras protein has to be prenylated in order for activation of this pathway to occur, making statin drug treatment a viable option as a cancer treatment. This is because it acts as a regulator of the mevalonate pathway which is upstream of protein prenylation. It is thus vital to understand these pathways at both the gene and protein level in different p53 mutants to further understand if simvastatin is indeed a drug with anti-cancer properties and can be used to target cancers with p53 mutation. The goal of this project is to study the biochemistry behind the mutation of p53's sensitivity to statin. With this information we can create a possible signature for those who could benefit from Simvastatin drug treatment as a possible targeted treatment for p53 mutant cancers.
ContributorsGrewal, Harneet (Co-author) / Loo, Yi Jia Valerie (Co-author) / Anderson, Karen (Thesis director) / Blattman, Joseph (Committee member) / Ferdosi, Shayesteh (Committee member) / Department of Psychology (Contributor) / School of Life Sciences (Contributor) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
While women in higher income countries can expect to survive a diagnosis of breast cancer, women in lower- and middle-income countries such as Bangladesh have mortality rates near 50%, suggesting that there are significant barriers to care seeking for breast problems. Given limited literature on barriers to care among native, rural South Asian populations, this study thus sought to understand 1) the impacts of breast problems on women and their families, including the extent of abuse among women with breast problems, and 2) the barriers and facilitators of care for women with breast problems in rural Bangladesh.
Sixty-three study participants (43 women and 20 men) were interviewed about their experiences. Interviewers elicited barriers to care, facilitators of care, and questions about the attitudes and behaviors of family and community members were in structured interviews.
The study found that breast problems and their treatment put significant resource and emotional strains on the family. Furthermore, over a third of women in this study reported abuse of some kind, with emotional abuse, neglect, and abandonment being the most frequently reported.
The study reinforced barriers to care identified in the literature for South Asian populations, but only a quarter of participants reported stigma of any kind. Lack of knowledge about breast cancer and inability to pay for care were the most frequently reported barriers, followed by access to care and fear of treatment. Facilitators of care among women who received a biopsy point to the importance of support by the husband and husband’s family, as well as the ability to identify economic support for and knowledge about care.
This study contributes to the understanding of two overarching themes: structural violence and the value of women, as well as how these themes influence poor outcomes for women with breast cancer in rural Bangladesh. Suggestions for future studies and short and long-term interventions to address study findings are offered.
Sixty-three study participants (43 women and 20 men) were interviewed about their experiences. Interviewers elicited barriers to care, facilitators of care, and questions about the attitudes and behaviors of family and community members were in structured interviews.
The study found that breast problems and their treatment put significant resource and emotional strains on the family. Furthermore, over a third of women in this study reported abuse of some kind, with emotional abuse, neglect, and abandonment being the most frequently reported.
The study reinforced barriers to care identified in the literature for South Asian populations, but only a quarter of participants reported stigma of any kind. Lack of knowledge about breast cancer and inability to pay for care were the most frequently reported barriers, followed by access to care and fear of treatment. Facilitators of care among women who received a biopsy point to the importance of support by the husband and husband’s family, as well as the ability to identify economic support for and knowledge about care.
This study contributes to the understanding of two overarching themes: structural violence and the value of women, as well as how these themes influence poor outcomes for women with breast cancer in rural Bangladesh. Suggestions for future studies and short and long-term interventions to address study findings are offered.
ContributorsSteiness, Heather Lynn Story (Author) / Hruschka, Daniel J (Thesis advisor) / Wutich, Amber (Committee member) / Ginsburg, Ophira (Committee member) / Arizona State University (Publisher)
Created2016
Description
Breast cancer is the second leading cause of disease related death in women, contributing over
40,000 fatalities annually. The severe impact of breast cancer can be attributed to a poor
understanding of the mechanisms underlying cancer metastasis. A primary aspect of cancer
metastasis includes the invasion and intravasation that results in cancer cells disseminating from
the primary tumor and colonizing distant organs. However, the integrated study of invasion and
intravasation has proven to be challenging due to the difficulties in establishing a combined tumor
and vascular microenvironments. Compared to traditional in vitro assays, microfluidic models
enable spatial organization of 3D cell-laden and/or acellular matrices to better mimic human
physiology. Thus, microfluidics can be leveraged to model complex steps of metastasis. The
fundamental aim of this thesis was to develop a three-dimensional microfluidic model to study the
mechanism through which breast cancer cells invade the surrounding stroma and intravasate into
outerlying blood vessels, with a primary focus on evaluating cancer cell motility and vascular
function in response to biochemical cues.
A novel concentric three-layer microfluidic device was developed, which allowed for
simultaneous observation of tumor formation, vascular network maturation, and cancer cell
invasion/intravasation. Initially, MDA-MB-231 disseminated from the primary tumor and invaded
the acellular collagen present in the adjacent second layer. The presence of an endothelial network
in the third layer of the device drastically increased cancer cell invasion. Furthermore, by day 6 of
culture, cancer cells could be visually observed intravasating into the vascular network.
Additionally, the effect of tumor cells on the formation of the surrounding microvascular network
within the vascular layer was evaluated. Results indicated that the presence of the tumor
significantly reduced vessel diameter and increased permeability, which correlates with prior in vivo
data. The novel three-layer platform mimicked the in vivo spatial organization of the tumor and its
surrounding vasculature, which enabled investigations of cell-cell interactions during cancer
invasion and intravasation. This approach will provide insight into the cascade of events leading up
to intravasation, which could provide a basis for developing more effective therapeutics.
40,000 fatalities annually. The severe impact of breast cancer can be attributed to a poor
understanding of the mechanisms underlying cancer metastasis. A primary aspect of cancer
metastasis includes the invasion and intravasation that results in cancer cells disseminating from
the primary tumor and colonizing distant organs. However, the integrated study of invasion and
intravasation has proven to be challenging due to the difficulties in establishing a combined tumor
and vascular microenvironments. Compared to traditional in vitro assays, microfluidic models
enable spatial organization of 3D cell-laden and/or acellular matrices to better mimic human
physiology. Thus, microfluidics can be leveraged to model complex steps of metastasis. The
fundamental aim of this thesis was to develop a three-dimensional microfluidic model to study the
mechanism through which breast cancer cells invade the surrounding stroma and intravasate into
outerlying blood vessels, with a primary focus on evaluating cancer cell motility and vascular
function in response to biochemical cues.
A novel concentric three-layer microfluidic device was developed, which allowed for
simultaneous observation of tumor formation, vascular network maturation, and cancer cell
invasion/intravasation. Initially, MDA-MB-231 disseminated from the primary tumor and invaded
the acellular collagen present in the adjacent second layer. The presence of an endothelial network
in the third layer of the device drastically increased cancer cell invasion. Furthermore, by day 6 of
culture, cancer cells could be visually observed intravasating into the vascular network.
Additionally, the effect of tumor cells on the formation of the surrounding microvascular network
within the vascular layer was evaluated. Results indicated that the presence of the tumor
significantly reduced vessel diameter and increased permeability, which correlates with prior in vivo
data. The novel three-layer platform mimicked the in vivo spatial organization of the tumor and its
surrounding vasculature, which enabled investigations of cell-cell interactions during cancer
invasion and intravasation. This approach will provide insight into the cascade of events leading up
to intravasation, which could provide a basis for developing more effective therapeutics.
ContributorsNagaraju, Supriya (Author) / Nikkhah, Mehdi (Thesis advisor) / Ebrahimkhani, Mohammad (Committee member) / Kiani, Samira (Committee member) / Arizona State University (Publisher)
Created2017
Description
Identifying disease biomarkers may aid in the early detection of breast cancer and improve patient outcomes. Recent evidence suggests that tumors are immunogenic and therefore patients may launch an autoantibody response to tumor associated antigens. Single-chain variable fragments of autoantibodies derived from regional lymph node B cells of breast cancer patients were used to discover these tumor associated biomarkers on protein microarrays. Six candidate biomarkers were discovered from 22 heavy chain-only variable region antibody fragments screened. Validation tests are necessary to confirm the tumorgenicity of these antigens. However, the use of single-chain variable autoantibody fragments presents a novel platform for diagnostics and cancer therapeutics.
ContributorsSharman, M. Camila (Author) / Magee, Dewey (Mitch) (Thesis director) / Wallstrom, Garrick (Committee member) / Petritis, Brianne (Committee member) / Barrett, The Honors College (Contributor) / College of Liberal Arts and Sciences (Contributor) / Virginia G. Piper Center for Personalized Diagnostics (Contributor) / Biodesign Institute (Contributor)
Created2012-12
Description
Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths in females worldwide, accounting for 23% of all new cancer cases and 14% of all total cancer deaths in 2008. Five tumor-normal pairs of primary breast epithelial cells were treated for infinite proliferation by using a ROCK inhibitor and mouse feeder cells. Methods: Raw paired-end, 100x coverage RNA-Seq data was aligned to the Human Reference Genome Version 19 using BWA and Tophat. Gene differential expression analysis was completed using Cufflinks and Cuffdiff. Interactive Genome Viewer was used for data visualization. Results: 15 genes were found to be down-regulated by at least one log-fold change in 4/5 of tumor samples. 75 genes were found to be down-regulated in 3/5 of our tumor samples by at least one log-fold change. 11 genes were found to be up-regulated in 4/5 of our tumor samples, and 68 genes were identified to be up-regulated in 3/5 of the tumor samples by at least one-fold change. Conclusion: Expression changes in genes such as AZGP1, AGER, ALG11, and S1007 suggest a disruption in the glycosylation pathway. No correlation was found between Cufflink's Her2 gene-expression and DAKO score classification.
ContributorsHernandez, Fernando (Author) / Anderson, Karen (Thesis director) / Mangone, Marco (Committee member) / Park, Jin (Committee member) / Barrett, The Honors College (Contributor) / Department of Information Systems (Contributor)
Created2013-05
Description
Adaptive therapy utilizes competitive interactions between resistant and sensitive cells by keeping some sensitive cells to control tumor burden with the aim of increasing overall survival and time to progression. The use of adaptive therapy to treat breast cancer, ovarian cancer, and pancreatic cancer in preclinical models has shown significant results in controlling tumor growth. The purpose of this thesis is to draft a protocol to study adaptive therapy in a preclinical model of breast cancer on MCF7, estrogen receptor-positive, cells that have evolved resistance to fulvestrant and palbociclib (MCF7 R). In this study, we used two protocols: drug dose adjustment and intermittent therapy. The MCF7 R cell lines were injected into the mammary fat pads of 11-month-old NOD/SCID gamma (NSG) mice (18 mice) which were then treated with gemcitabine.<br/>The results of this experiment did not provide complete information because of the short-term treatments. In addition, we saw an increase in the tumor size of a few of the treated mice, which could be due to the metabolism of the drug at that age, or because of the difference in injection times. Therefore, these adaptive therapy protocols on hormone-refractory breast cancer cell lines will be repeated on young, 6-week old mice by injecting the cell lines at the same time for all mice, which helps the results to be more consistent and accurate.
ContributorsConti, Aviona (Author) / Maley, Carlo (Thesis director) / Blattman, Joseph (Committee member) / Seyedi, Sareh (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Ultrasound has become one of the most popular non-destructive characterization tools for soft materials. Compared to conventional ultrasound imaging, quantitative ultrasound has the potential of analyzing detailed microstructural variation through spectral analysis. Because of having a better axial and lateral resolution, and high attenuation coefficient, quantitative high-frequency ultrasound analysis (HFUA) is a very effective tool for small-scale penetration depth application. One of the QUS parameters, peak density had recently shown a promising response with the variation in the soft material microstructure. Acoustic scattering is arguably the most important factor behind different parametric responses in ultrasound spectra. Therefore, to evaluate peak density, acoustic scattering at different frequency levels was investigated. Analytical, computational, and experimental analysis was conducted to observe both single and multiple scattering in different microstructural setups. It was observed that peak density was an effective tool to express different levels of acoustic scattering that occurred through microstructural variation. The feasibility of the peak density parameter was further evaluated in ultrasound C-scan imaging. The study was also extended to detect the relative position of the imaged structure in the direction of wave propagation. For this purpose, a derivative parameter of peak density named mean peak to valley distance (MPVD) was developed to address the limitations of peak density. The study was then focused on detecting soft tissue malignancy. The histology-based computational study of HFUA was conducted to detect various breast tumor (soft tissue) grades. It was observed that both peak density and MPVD parameters could identify tumor grades at a certain level. Finally, the study was focused on evaluating the feasibility of ultrasound parameters to detect asymptotic breast carcinoma i.e., ductal carcinoma in situ (DCIS) in the surgical margin of the breast tumor. In that computational study, breast pathologies were modeled by including all the phases of DCIS. From the similar analysis mentioned above, it was understood that both peak density and MPVD parameters could detect various breast pathologies like ductal hyperplasia, DCIS, and calcification during intraoperative margin analysis. Furthermore, the spectral features of the frequency spectrums from various pathologies also provided significant information to identify them conclusively.
ContributorsPaul, Koushik (Author) / Ladani, Leila (Thesis advisor) / Razmi, Jafar (Committee member) / Holloway, Julianne (Committee member) / Li, Xiangjia (Committee member) / Liu, Yongming (Committee member) / Arizona State University (Publisher)
Created2022
Description
The TP53 tumor suppressor gene is the most frequently mutated gene in human cancers. In the highly aggressive triple negative breast cancer (TNBC), TP53 is mutated in 80% of cases. TNBC lacks viable drug targets, resulting in a low prognosis (12.2% 5 year survivability rate). As such, the discovery of druggable targets in TNBC would be beneficial. Mutated p53 protein typically occurs as a missense mutation and often endows cancer cells with gain of function (GOF) properties by dysregulating metabolic pathways. One of these frequently dysregulated pathways is the Hippo/Yes-associated protein-1 (YAP1)/WW Domain Containing Transcription Regulator 1 (TAZ) tumor suppressor pathway. This study therefore analyzed the involvement of the Hippo/YAP1/TAZ pathway in p53-mediated breast cancer cell invasion. From an RNA-seq screen in MCF10A cell lines harboring different TP53 missense mutations, each with a differing invasive phenotype, components of the Hippo pathway were found to correlate with cell invasion. To this end, the active and inactive forms of YAP1 and TAZ were studied. Phosphorylated (inactive) YAP1 and TAZ are retained in the cytoplasm and eventually degraded. Unphosphorylated (active) YAP1 and TAZ translocate to the nucleus to activate TEAD-family transcription factors, inducing cell survival and proliferation genes leading to increased cell invasion. Using quantitative western blot analysis, it was found that inactive TAZ expression was lower in the most invasive cell lines and higher in the least invasive cell lines (p = 0.003). Moreover, the ratio of inactive TAZ protein to total TAZ protein was also shown to be predominantly lower in the invasive cell lines compared to the non-invasive lines (p = 0.04). Finally, active TAZ expression was primarily higher in p53-mutant invasive cell lines and lower in non-invasive p53 mutant cells. Additionally, although YAP1 and TAZ are thought to be functionally redundant, the pattern seen in TAZ was not seen in the YAP1 protein. Taken together, the results demonstrated here suggest that TAZ holds a more dominant role in governing TNBC cell invasion compared to YAP1 and further highlights TAZ as a potential therapeutic target in TNBC.
ContributorsGrief, Dustin (Author) / LaBaer, Joshua (Thesis advisor) / Anderson, Karen (Committee member) / Nikkhah, Mehdi (Committee member) / Arizona State University (Publisher)
Created2022
Description
Breast cancer is one of the most common types of cancer worldwide. Early detection and diagnosis are crucial for improving the chances of successful treatment and survival. In this thesis, many different machine learning algorithms were evaluated and compared to predict breast cancer malignancy from diagnostic features extracted from digitized images of breast tissue samples, called fine-needle aspirates. Breast cancer diagnosis typically involves a combination of mammography, ultrasound, and biopsy. However, machine learning algorithms can assist in the detection and diagnosis of breast cancer by analyzing large amounts of data and identifying patterns that may not be discernible to the human eye. By using these algorithms, healthcare professionals can potentially detect breast cancer at an earlier stage, leading to more effective treatment and better patient outcomes. The results showed that the gradient boosting classifier performed the best, achieving an accuracy of 96% on the test set. This indicates that this algorithm can be a useful tool for healthcare professionals in the early detection and diagnosis of breast cancer, potentially leading to improved patient outcomes.
ContributorsMallya, Aatmik (Author) / De Luca, Gennaro (Thesis director) / Chen, Yinong (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Computer Science and Engineering Program (Contributor)
Created2023-05
Description
Globally, breast cancer is the most common cancer in women. The disease and treatment cause many unfavorable symptoms such as fatigue, pain, and psychological stress. Research suggests that stress may negatively impact survival and recurrence outcomes of breast cancer patients. Cognitive-behavioral stress management (CBSM) programs have been found to improve these outcomes. In this thesis, I propose using virtual reality as a tool for CBSM to improve symptoms and outcomes for non-metastatic breast cancer patients.
ContributorsPodsiadlo, Katherine (Author) / Hartwell, Leland (Thesis director) / Andersen, Karen (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / Department of Psychology (Contributor)
Created2023-05