Browsing by Subject "breast cancer"
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Item Beyond the "Angelina Effect": A Longitudinal Analysis of Celebrity Breast Cancer Disclosures' Impact on News Media and Public Breast Cancer Information Seeking Outcomes(2017-07) LoRusso, SusanA long research tradition exists investigating the content of news coverage of celebrity breast cancer disclosures and, to a greater extent, the impact these personal health narratives have on public cancer-related outcomes. However, the bulk of this research focuses on specific, large-scale media events, such as Angelina Jolie’s 2013 BRCA disclosure. The attention to individual disclosures provide insight about the specific media event, but does not further knowledge about the larger phenomenon of celebrity cancer disclosures. To go beyond the Angelina effect, this dissertation addresses three overarching research questions: 1) What breast cancer-related messages are present in media coverage of celebrity breast cancer disclosures; 2) do these messages impact public cancer-related behavioral outcomes (i.e., online breast cancer information seeking); and 3) are there attributes of the celebrity that predict media and public outcomes? To address these questions, first, 110 individual celebrity breast cancer disclosures between 2005 and 2016 were systematically identified. Then, two longitudinal studies were conducted. To address the first question, Study 1 used computer assisted and hand coded procedures to assess the presence of episodic frames (defined as containing information specific to the celebrity and her experience with breast cancer) and thematic frames (defined as including population and subpopulation breast cancer information [e.g., prevalance, risk, survial rates]). In addition, the presence of seven content categories classified as misinformation (defined as information which is innaccurate, misleading, or oversimplified) in news coverage was assessed. Results demonstrated that 80% of the news articles were written with an episodic frame, and 20% were written with a thematic frame, indicating very little information beyond the celebrity’s own experience with breast cancer was conveyed to the public. However, misinformation was largely absent in the news coverage—only misinformation pertaining to early breast cancer detection and mastectomy decisions was present in 10% or more of the news coverage. Study 2 attempts to determine if news content impacts information seeking by using the framing outcomes from Study 1 to predict Google Trends search query outcomes. Due to the disparate rates in the presence of episodic and thematic frames this dissertation is unable to provide support linking content and online breast cancer information seeking outcomes. However, time series models suggest that media coverage of celebrity breast cancer disclosures in the aggregate have a distal impact on the public’s breast cancer information seeking outcomes. For example, some analyses suggested effects happened as late as 17 months after news coverage of the disclosure. Yet the nature of these trends may be a function of the data. Establishing if celebrity attributes can predict media and public outcomes was done through a moderation analysis of the results of Study 1 and Study 2. Specifically, the extent to which the presence of episodic and thematic and misinformation were present and statistically significant information seeking models were examined as a function of the celebrity’s age, career type, breast cancer-event type, and level of celebrity status (defined as the degree of fame the celebrity achieved at the time of disclosure). Eighty-seven percent of thematic frames present were in news coverage of celebrities at the highest levels of fame. Specific categories in the age, career-type, and level of celebrity status variables predicted the presence of misinformation. Some preliminary evidence suggests level of celebrity status may predict online breast cancer information seeking outcomes. The implications of the dissertation’s findings for health communication research, mass media effects research, and professional health communicators are discussed.Item Breast Cancer Screening: What you need to know as an informed patient(2008-09-02) Prebil, SarahCurrently, self breast exams as well as clinical breast exams are viewed as possibly cost-saving and life-saving practices for women around the world. However, given the analysis of two large scale studies, self-breast exams accomplish neither of these goals. In fact, these breast exams may be causing more harm than no intervention at all because of unnecessary breast biopsies. Therefore, regular self breast examination cannot be recommended. For screening, women should be aware of any changes in their breasts and see a doctor if a change occurs. Starting at age 40, women should get yearly mammograms.Item Cardiovascular Disease In Cancer Survivors(2023) Polter, ElizabethOver 18 million cancer survivors are living in the United States. Cancer survivors are at high risk for numerous adverse events, including cardiovascular disease (CVD). As the community of cancer survivors grows, there is a need to disentangle the complex causal relationships between cancer and CVD.In our first two manuscripts, we investigated two potential causes of CVD in cancer survivors. Manuscript 1 evaluated the associations between cancer, T-Cell immunosenescence (immune system aging), and CVD using data from the Health and Retirement Study. Prevalent cancer was strongly associated with T-cell immunosenescence, with stronger associations among participants who received chemotherapy and radiation. However, T-cell Immunosenescence was not prospectively associated with CVD or cancer. For Manuscript 2, we used the Marketscan® administrative healthcare claims databases to estimate the cardiovascular risk associated with the use of two hormone therapies, aromatase inhibitors (with ovarian suppression) and tamoxifen in premenopausal female breast cancer survivors. Although CVD events were rare in this population, enrollees who used aromatase inhibitors with ovarian suppression had an elevated risk of CVD compared to those who used tamoxifen. Finally, Manuscript 3 assessed the performance of the Pooled Cohort Equations (PCEs), risk prediction tools used to estimate ten-year cardiovascular risk and prescribe interventions. Analyses included cancer survivors and cancer-free participants in the Atherosclerosis Risk in Communities Study. Although the PCEs overestimated CVD risk in each group, we found no evidence that prediction differed by cancer history. Together, these findings provide insights that can be used to improve cardiovascular healthcare and prevention for cancer survivors.Item Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer(2016-10) Chuntova, PollyThe studies presented in this thesis demonstrate a novel link between activation of the FGFR pathway, alterations of the tumor microenvironment and tumor immune response in mammary tumorigenesis. These studies are the first to demonstrate that FGFR signaling in epithelial cells leads to accumulation of the ECM component hyaluronan (HA) through increased production of pro-inflammatory cytokines and activation of the STAT3 pathway. Therapeutic inhibition of STAT3 in vivo reduced HA accumulation, which correlated with reduced tumor burden. Nonetheless, STAT3 inhibition did not result in tumor regression, suggesting that additional pro-tumorigenic mechanisms are able to sustain tumor growth. Previous work has shown that FGFR1 activation leads to rapid recruitment of macrophages with pro-tumorigenic functions. We hypothesized that as TAMs differentiate in the presence of FGFR1-driven IL-6 family of cytokines, the STAT3 signaling pathway would be activated and would influence TAM differentiation. Therefore, further studies focused on delineating the STAT3-dependent phenotype and function of mammary TAMs. Utilizing a mouse model of genetic STAT3 ablation within myeloid cells demonstrated decreased tumor latency and increased tumor growth rate in conditional-STAT3∆/∆ mice compared to control animals. These results provide evidence to the hypothesis that STAT3 activation in different tumor and immune cell populations can result in both pro- and anti-tumor phenotypes, and detailed understanding of these mechanisms is necessary for developing effective therapeutic approaches.Item CONTRIBUTIONS OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION PROTEINS TO TUMOR-ASSOCIATED MACROPHAGE FUNCTION IN BREAST CANCER(2021-05) Jesser, EmilyThe Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is activated in breast cancer and when hyperactive, can influence uncontrollable proliferation and inflammation. Therapies in clinical trials for breast cancer aim to inhibit JAK/STAT to turn off the “switch” in tumors signaling for growth and proliferation. The studies performed in this dissertation investigate how these inhibitors impact the tumor microenvironment. We have demonstrated that although inhibition of the JAK/STAT pathway may act on primary tumor cells directly, this alters a delicate balance in the microenvironment that leads to macrophage-mediated tumor cell therapeutic resistance and proliferation. Using genetic models of STAT3 or STAT5-specific deletion, we sought to determine the contributions of these individual transcription factors to macrophage function in the tumor microenvironment. As it has not be well-studied in breast cancer to date, we further investigated how STAT5 signaling regulates tumor-associated macrophages. We demonstrated disruption of STAT5 signaling in macrophages impedes their expression of genes associated with the anti-tumor immune response, as well as increased factors related to tissue remodeling and enhanced metastatic processes. Taken all together, these studies demonstrate the critical role macrophages play in influencing the progression or restraint of the spread of breast cancer. Further understanding how specific JAK/STAT signaling components control pro- and anti-tumor responses in these cells will be vital for determining a patient’s treatment course as well as allowing for the potential discovery of novel therapeutics.Item Diagnosis, treatment, and survival among older women with breast cancer: the effect of pre-existing mental illness.(2021-04) Bhattacharya, ManamiBackgroundPeople with a mental illness die 8-25 years earlier than people without a mental illness. Among women, decreased life expectancy is partially due to higher mortality from breast cancer; women with mental illnesses experience up to 367% increased hazards of mortality after breast cancers compared to women without mental illnesses. Yet, with timely detection and appropriate treatment breast cancer is very survivable. ObjectivesThis research focuses on how a pre-existing diagnosis of mental illness affects breast cancer outcomes across the cancer continuum, focusing on differences in stage of diagnosis, receipt of guideline-concordant care, and survival. I also examine whether outcomes vary by type and severity of mental illness. Finally, I evaluate whether the impact of mental illness varies by race, arguing that having marginalized identities associated with multiple forms of oppression may worsen outcomes. MethodsThis project uses the linked Surveillance and Epidemiology and End Results (SEER) cancer registry and Medicare claims (SEER-Medicare), a data national source that captures a significant proportion of breast cancer cases nationally among women over 65 years old. Mental illness is defined and categorized as having a diagnosis of serious mental illness (schizophrenia, bipolar disorder, depression with psychosis, and other psychotic disorders); depression or anxiety; and other mental illnesses excluding cognitive disabilities, in the two years prior to cancer diagnosis. Outcomes examined include AJCC staging, receipt of NCCN guideline-concordant care, focusing on surgery, radiation, and chemotherapy, and months of survival. A total of 96,034 women were included, though sample sizes vary depending on the analysis. ResultsPre-existing mental illnesses are common for women diagnosed with breast cancer. Overall, I found that 28.6% of women in this study had at least one diagnosis of a mental illness in the two years prior to their breast cancer diagnosis and 1.7 % had a serious mental illness. Women with SMI are more likely to be diagnosed with Stage II or III breast cancers than women without mental illnesses and women with depression or anxiety are less likely to be diagnosed with Stage IV cancers. In terms of treatment, I find that among women with AJCC stage I-III cancer, where either a mastectomy or breast conserving surgery and a full course of radiation is recommended, women with SMI less likely to receive surgery than women without. Women with mental illnesses (regardless of type) have a higher risk of not completing radiation after breast conserving surgery. Among women with AJCC stage I-III triple negative or HER2+ cancers, women with SMI are more likely to not complete surgery, radiation, and chemotherapy. Finally, I find that women with mental illnesses (regardless of type) have higher risks for mortality after cancer from both breast cancers and other causes, and that this risk is not entirely explained by stage of diagnosis and treatment received. Differences in survival are greatest for persons with SMI. I also investigated whether the effects of mental illness on cancer outcomes vary by race/ethnicity and find evidence that Black and Hispanic women may have especially high risks for later staging of breast cancer, incomplete treatment, and higher mortality. ConclusionsBreast cancer and mental illness are both common illnesses facing older women in the United States. This work provides new insights into issues of equity around breast cancer outcomes for older women with mental illnesses and provides entry points for considering interventions that will improve outcomes. This work also provides information for areas where inequities among Black and Hispanic women with mental illnesses experiencing breast cancer should be investigated further.Item Incidence patterns, care continuum and impact of treatment on survival among women with breast cancer in Ghana and the United States(2021-05) Mburu, EddahBreast cancer is the most commonly diagnosed cancer among women worldwide. Of the five breast cancer subtypes, triple negative breast cancer (TNBC) is the most aggressive subtype. Black women in the US and Ghana are more likely to be diagnosed with TNBC, at young ages and advanced stages. Combining information from Ghana and the US, this project identified the breast cancer care continuum in Ghana, examined the breast cancer incidence patterns in Ghana and the US and assessed the optimal surgical treatment for TNBC. In the first manuscript, we examined how women in Ghana navigate the healthcare system and factors that influence their decisions and ability to seek and access breast cancer care. We interviewed thirty-one women diagnosed with breast cancer in Kumasi, Ghana. Based on the findings from the interviews, we presented a framework showing specific steps in the pathways and how women transition from one step to another. In the second manuscript, we assessed factors explaining the younger age at breast cancer diagnosis among Ghanaian women compared to women in the US. To achieve these aims we analyzed breast cancer data from the Kumasi Cancer Registry, the only population-based cancer registry in Ghana, and compared it to the US Surveillance, Epidemiology and End Results (SEER) data. Population age structure, screening and cohort effects explain the younger age at breast cancer diagnosis among women in Ghana In the third manuscript, we examined whether the poor prognosis of TNBC warrants a more aggressive surgical approach and whether there is value in expanded use of radiation therapy among women with TNBC who receive mastectomy. We found that breast conserving surgery followed by radiotherapy is an effective treatment for women with early-stage TNBC. Findings from this dissertation are timely due to the rapidly rising burden of breast cancer in sub-Saharan Africa and persistent disparities in the US.Item Metabolic-response assessment of metastatic murine breast cancer in 2D and 3D cultures using intrinsic NADH as a natural biomarker(2019-08) Cong, AnhThe majority of in vitro studies of living cells are routinely conducted in a two-dimensional (2D) monolayer culture towards pathophysiological investigation, drug screenings, and cancer diagnostics. There is strong evidence, however, that suggests cellular behavior and metabolism in 2D cell culture is too simplistic of a model as compared with those in vivo tumor cells. In this project, we hypothesize that cancer cell metabolism and metabolic responses to external stimuli (e.g. drug treatments) are distinctly different in threedimensional (3D), tumor-like model as compared with that of the conventional 2D monolayer culture. To test this hypothesis, we employed two-photon (2P) fluorescence lifetime imaging microscopy (2P-FLIM) and time-resolved 2P-fluorescence anisotropy of the reduced nicotinamide adenine dinucleotide (NADH) in metastatic murine breast cancer cells 4T1. In addition, we investigated the cellular metabolic response of 4T1 cells in 2D monolayer and 3D collagen matrix cultures to drug treatment using two novel metabolic drugs, namely MD1 and TPPBr. Both 2P-FLIM and complementary time-resolved anisotropy approaches reveal significant differences between metabolic activities of 4T1 cells in 2D and 3D cultures. Our results suggest that these 4T1 cells in 3D culture adapt an oxidative shift but glycolysis dominances the metabolic state of 2D cells. In addition, 4T1 cells in 3D culture appear to adapt more quickly and exhibit enhanced metabolic activities in response to drug treatment. In contrast, 4T1 cells in 2D monolayer culture exhibit a mute response and are less sensitive to drug treatments. While the tumor-like 3D collagen matrix model may not be an exact replica of in vivo tumors, these studies represent a critical step towards the development of a fundamental understanding of cellular behaviors and metabolism in the more complex in vivo models. These studies would also help advance our understanding of how the cancer cell heterogeneity and microenvironmental conditions impact metabolism and metabolic plasticity in tumor growth and metastatic progression.Item Pathway to metastasis: carcinoma dissemination via organized collagen tracks(2017-12) Ray, ArjaA vital part of the metastatic cascade that leads to cancer-related deaths is the initial dissemination of cancer cells from a confined lesion into neighboring tissue by migration and invasion. Breast and pancreatic carcinomas are often associated with increased deposition of collagen-I, which can assemble into aligned fiber tracks in mature breast tumors. Such aligned tracks provide contact guidance cues for directed cancer cell migration and dissemination leading to increased invasion, metastasis and decreased disease-free survival in breast cancer patients. Using multiphoton imaging, we demonstrate that organized collagen architectures develop in the pancreatic ductal adenocarcinoma (PDA) stroma even at the pre-invasive stage with single cells and multicellular clusters interacting with aligned collagen tracks in vivo. Mimicking the collagen patterns with microfabricated substrates, we show that for single cells, aligned architectures induce constrained focal adhesion maturation and associated F-actin alignment, consequently orchestrating anisotropic traction stresses that drive cell orientation and directional migration. While such interactions allow single mesenchymal-like cells to spontaneously “sense” and follow topographic alignment, intercellular interactions within epithelial clusters counteract anisotropic cell-substratum forces, resulting in substantially lower directional response. Indeed, anisotropic cell-substratum interactions from organized periductal collagen may contribute to cell extrusion and dissemination from pre-invasive ductal epithelia in PDA. Such contact guided spreading of cancer cells may be inhibited by dismantling the fiber architecture, diminishing its density or by abrogating cell-ECM interactions. To validate our findings in 3D we engineered novel in vitro substrates using a simple method to align 3D collagen gels by guided cellular compaction, to produce highly aligned, acellular collagen constructs as a controlled microenvironment in vitro. Additionally, we integrated the aligned collagen matrices to cell dense tumor-like plugs, allowing tracking of the temporal evolution of the advancing invasion fronts over several days. Live cell imaging and analysis of 3D cell migration revealed profoundly enhanced motility in aligned collagen matrices for the putative cancer stem cell subpopulation. Heterogeneity in cell migration behavior was also observed between cells at the leading edge and those within the tumor boundary, thus demonstrating the versatility of these platforms in capturing the dynamics of contact guided carcinoma dissemination.Item Queering and Intersectionalizing Health Services Research: Structural Influences on Minoritized Sexual and Gender Populations’ Mammogram Usage(2024) Sarkin, CourtneyBreast/chest cancer screening, such as mammography, is recommended to detect breast/chest cancer in its earlier stages; a growing body of research on breast/chest cancer screening suggests that sexually and gender minoritized (SGM) populations experience unique barriers to timely detection of breast/chest cancer screening. A notable barrier to preventive health service use among SGM communities is cisheteropatriarchy, yet many SGM people also have overlapping experiences of oppression from structural racism and urbanism. Little research explores how structural oppression manifests for mammogram usage among those with minoritized sexual orientations, gender identities and races and ethnicities and marginalized by rurality. Using 2022 Behavioral Risk Factor Surveillance System (BRFSS) data, this research is among the first to explore the relationship between mammogram usage and the intersections of sexual orientation, gender identity, rurality, race and ethnicity. This dissertation presents results on mammogram usage for these populations; further, it aims to bring critical social theories, including queer theory and intersectionality, into conversation with health services research. Lastly, I construct a composite measure of state-level structural cisheteropatriarchy and examine its relationship to mammogram usage with specific attention to the impact of structural cisheteropatriarchy on SGM communities. This research proposes a structural intersectionality approach to studying inequities in mammogram usage for minoritized sexual and gender populations.Item REGULATION OF HYALURONAN TURNOVER IN THE DEVELOPING MAMMARY GLAND AND ITS CONTRIBUTION TO CD44 SIGNALING AND INFLAMMATION IN BREAST CANCER(2022-04) Witschen, PatriceCancer has been compared to a chronic wound unable to heal, as the balance is tipped in favor of pro-tumor inflammation. Therefore, it is important to understand how cancer cells interact with and alter their environment to ultimately support disease progression. Hyaluronan (HA) is of particular interest as it is a large glycosaminoglycan of the extracellular matrix that has anti-inflammatory effects under physiologic conditions. However, under conditions of organismal stress, an increase in HA deposition and fragmentation occurs, yet it is unknown how HA deposition impacts malignant progression. We begin by comparing HA machinery within murine mammary glands to aid in our understanding of its aberrant regulation in tumors. To our knowledge, we are the first to characterize HA deposition within the murine mammary gland across key stages of development. Additionally, our findings support a novel role for macrophages in homeostatic and aberrant HA turnover. Furthermore, we demonstrate that breast cancer cells promote cancer-associated inflammation through HA-CD44 interactions, and this axis contributes to early tumor formation. Importantly, our results are supported by data from human breast cancer cases, where increased hyaluronan synthase 2 expression significantly correlates with an inflammatory gene signature. Finally, we define a link between fibroblast growth factor receptor (FGFR)-mediated activation of HA synthesis and HA-CD44 driven macrophage recruitment during early tumorigenesis. Overall, this work establishes essential groundwork for future studies aiming to identify key targets and new therapeutic approaches for the treatment of breast cancer. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.Item Targeting Downstream Effectors of IGF/Insulin Signaling System in Human Breast Cancer(2015-08) Yang, YuzheTransmembrane growth factor receptors mediate signaling through multiple intracellular pathways. In breast cancer cells, the type I insulin-like growth factor receptor (IGF-IR) has been implicated of tumorigenicity, proliferation, and metastasis. However, clinical trials with anti-IGF-IR monoclonal antibodies have generally been disappointing, partially due to lack of predictive biomarkers or adaptive compensational pathways activated when IGF-IR is blocked. To determine whether IGF-IR inhibition could be enhanced by disrupting other pathways, here we sought to investigate novel molecular targets downstream of IGF-IR signaling system and evaluate combination efficacy in estrogen receptor (ER) positive, basal-like, and endocrine resistant human breast cancer cell lines in vitro. The first part of this dissertation focuses on characterization of the mechanism of action and evaluation of therapeutic efficacy of a novel insulin receptor substrate 1 and 2 (IRS1/2) targeting compound NT157 in multiple breast cancer types. IRS1/2 transduce signaling from IGF-IR and insulin receptor (InR) to mediate the IGF effects on breast cancer cell biology. IRS-1 plays a critical role in cancer cell proliferation in ER positive breast cancers while IRS-2 is the predominate isoform in many basal-like breast cancers and is associated with motility and metastasis. NT157, a small-molecule tyrphostin, has been shown to downregulate IRS proteins in several model systems. In ER positive and basal-like breast cancer cells, NT157 treatment suppressed IRS protein expression in a dose dependent manner. NT157 treatment did not affect IGF-I, IGF-II, and insulin induced activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) in the short term, but longer exposure to NT157 inhibited the activation of these signaling pathways. The ability of NT157 to induce serine phosphorylation of IRS proteins was dependent on MAPK activation. Serine phosphorylation resulted in disassociation between IRS proteins and their receptors resulting in IRS degradation. In ER positive breast cancer cells, NT157 also resulted in cytoplasmic ERα downregulation likely because of disruption of an IRS-1-IGF-IR/InR/ERα complex. NT157 decreased S phase fraction after IGF/insulin treatment in ER positive breast cancer cells with inhibition of monolayer and anchorage-independent growth. NT157 downregulation of IRS protein expression also sensitized ER positive breast cancer cells to rapamycin. Moreover, NT157 inhibited the growth of tamoxifen resistant ER positive breast cancer cells. In basal-like breast cancer cells, NT157 repressed the proliferation (G2/M abrogation) and migration through downregulation of IRS1/2 protein. Given that both IGF-IR and InR play a role in cancer biology, targeting of IRS adaptor proteins may be a more effective strategy to inhibit these receptors. In the second part of this dissertation, we highlight an amino acid transporter �" xC- to be a novel co-target in addition to IGF-IR targeted therapies in ER positive breast cancer cells. IGF-I stimulates growth of normal and malignant cells. Increased uptake of amino acids after activation of IGF-IR signaling has been well characterized. xCT (SLC7A11) encodes the functional subunit of the heterodimeric plasma membrane transport system xC- critical for the cellular uptake of cystine, generation of glutathione, and modulation of cellular redox control. Here, we show that IGF-I induced xCT mRNA, protein expression, and function in ER positive breast cancer cell lines in an IRS-1 dependent manner. IGF-I further controlled cellular redox level through the xC- transporter. IGF-I-stimulated monolayer and anchorage-independent growth was suppressed by reducing xCT expression or by treating cells with the xC- chemical inhibitor sulfasalazine (SASP). Anchorage-independent growth assays showed that disruption of xC- function by SASP sensitized cells to anti-IGF-IR inhibitors (monoclonal antibody huEM164 and tyrosine kinase inhibitor NVP-AEW-541). The growth suppressive effects of SASP were reversed by the ROS scavenger N-acetyl-L-cysteine. Thus, IGF-I promotes the proliferation of ER positive breast cancer cells by regulating xC- transporter function to protect cancer cells from ROS in an IRS-1 dependent manner. Our findings also imply that inhibition of xC- transporter function combined with anti-IGF-IR agents may have synergistic therapeutic effect. The third part of this dissertation aims at thoroughly investigating the IGF’s regulation on Nuclear factor-erythroid 2-related factor 2 (Nrf2) in ER+ breast cancers and evaluating Nrf2 as a target in triple negative / basal-like (TNBC) breast cancers. Nrf2 is a key transcriptional activator that mediates cellular antioxidant response by initiating expression of various anti-oxidative and anti-inflammation genes. Constitutive stabilization of Nrf2 has been observed in many human cancers and confers chemo- and radio-resistance of cancer cells. We examined Nrf2 expression and function in a panel of breast cancer cell lines. mRNA expression of Nrf2 was higher in the TNBC/basal-like cell lines MDA-MB-231 and MDA-MB 436 compared to immortalized breast epithelial cells and other types of breast cancers. In estrogen receptor positive (ER+) breast cancer cells MCF-7 and T47D where basal level of Nrf2 were low, IGF signaling system regulated Nrf2 expression, nucleus translocation and ARE-binding capability. Downregulation of Nrf2 sensitized ER+ cells’ response towards irradiation in the presence of IGF-I ligand. shRNA knock-down of Nrf2 in MDA-MB-231 and MDA-MB-436 TNBC cells showed decreased mRNA expression of multiple Nrf2 regulated anti-oxidant and pentose phosphate pathway genes, enhanced basal levels of cellular reactive oxygen species, impaired mitochondrial function and reduced S phase entry. Cells with decreased Nrf2 had reduced cell growth in monolayer, anchorage independent, and 3-dimensional growth assays. In addition, Nrf2 suppression reduced cell migration. Nrf2 down-regulated MDA-MB-231 cells also showed increased response towards ionizing radiation in clonogenic and soft agar assays. Furthermore, reduced Nrf2 expression decreased the number of stem-like (CD44+/CD24-) population in MDA-MB-231 cells possibly through xC- transporter regulation. Thus, IGF signaling induces Nrf2 expression and function, which suggests Nrf2 could be a therapeutic co-target in combination to anti-IGF treatment. Nrf2 regulates various aspects of the malignant phenotype in TNBC that inhibition of Nrf2 might be a therapeutic option for TNBC. Taken together, the data in this thesis demonstrate that IGF-IR activation stimulates multiple downstream effectors important for breast cancer cell biology. Inhibition of selected downstream signaling molecules alone or in combination with anti-IGF-IR drugs is likely to better therapeutic outcomes in breast cancers.Item Travel And Treatment Among Breast Cancer Patients: A Population-Based Analysis(2020-04) Longacre, ColleenTreatment choices for patients with breast cancer require balancing a variety of considerations, but travel distance may create barriers to accessing specific treatments and impact patient choices and outcomes. This dissertation uses novel methods to explore travel burden and evaluate the relationship between travel distance and: 1) surgical choice (mastectomy or breast-conserving surgery (BCS), 2) optimal receipt of radiation, and 3) breast reconstruction among a population-based national sample of newly diagnosed breast cancer patients. We use data from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Our study cohort consists of breast cancer patients newly diagnosed between 2004 and 2013. We use Google Maps and ArcGIS to calculate driving distances and driving times to the nearest available treatment facility. We find that patients living in rural areas traveled on average nearly three times as far for radiation treatment as those from urban areas (40.8 miles vs. 15.4 miles), and their nearest facility was more than four times farther away (21.9 miles vs. 4.8 miles). Disease severity (stage, grade, etc.) was not significantly associated with actual or minimum travel distance. We also find that women living farther from radiation facilities (>50 miles vs. <10 miles) were more likely to undergo mastectomy vs. BCS (OR: 1.48, 95% CI: 1.22, 1.79). Among those who underwent BCS, women living farther from radiation facilities were less likely to complete any RT (OR: 1.72, 95% CI: 1.32, 2.23) or the full recommended course of RT (OR: 1.79, 95% CI: 1.24, 2.60), and were thus more likely to receive guideline-discordant treatment. Women receiving guideline-discordant treatment had worse overall (HR: 1.50, 95% CI: 1.42, 1.57) and breast-cancer specific survival (HR: 1.44, 95% CI: 1.29, 1.60) compared to women receiving guideline-concordant treatment. Finally, we find that increased distance to the nearest reconstruction provider was associated with decreased odds of reconstruction (p<0.001) among mastectomy patients and increased odds of delayed vs. immediate reconstruction among reconstruction patients (p=0.0003). Women living >50 miles away from a reconstruction provider had 51% lower odds of immediate reconstruction (OR: 0.49, 95% CI: 0.39, 0.62) and 93% higher odds of delayed reconstruction (OR: 1.93, 95% CI: 1.03, 3.60) compared to women living within 10 miles of a reconstruction provider. Method of reconstruction was also highly correlated with geography. Increases in reconstruction rates were greater among urban patients, widening the disparity in reconstruction rates among urban vs. rural patients. Taken together, these results suggest that travel burden may be contributing to patients making suboptimal treatment decisions, which in turn contribute to suboptimal survival and patient-centered (quality of life) outcomes. Clinicians, policymakers, and patient advocates should explore social support models, such as lodging and transportation support, and service delivery models, such as shorter treatment regimens, aimed at reducing travel burden and improving guideline-concordant treatment among this patient population.