Browsing by Subject "breast cancer"
Now showing 1 - 13 of 13
- Results Per Page
- Sort Options
Item Open Access An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1.(Cancers, 2022-08) Doheny, Daniel; Manore, Sara; Sirkisoon, Sherona R; Zhu, Dongqin; Aguayo, Noah R; Harrison, Alexandria; Najjar, Mariana; Anguelov, Marlyn; Cox, Anderson O'Brien; Furdui, Cristina M; Watabe, Kounosuke; Hollis, Thomas; Thomas, Alexandra; Strowd, Roy; Lo, Hui-WenThe goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.Item Open Access Automatic Planning of Whole Breast Radiation Therapy Using Machine Learning Models.(Frontiers in Oncology, 2019-01) Sheng, Yang; Li, Taoran; Yoo, Sua; Yin, Fang-Fang; Blitzblau, Rachel; Horton, Janet K; Ge, Yaorong; Wu, Q JackiePurpose: To develop an automatic treatment planning system for whole breast radiation therapy (WBRT) based on two intensity-modulated tangential fields, enabling near-real-time planning. Methods and Materials: A total of 40 WBRT plans from a single institution were included in this study under IRB approval. Twenty WBRT plans, 10 with single energy (SE, 6MV) and 10 with mixed energy (ME, 6/15MV), were randomly selected as training dataset to develop the methodology for automatic planning. The rest 10 SE cases and 10 ME cases served as validation. The auto-planning process consists of three steps. First, an energy prediction model was developed to automate energy selection. This model establishes an anatomy-energy relationship based on principle component analysis (PCA) of the gray level histograms from training cases' digitally reconstructed radiographs (DRRs). Second, a random forest (RF) model generates an initial fluence map using the selected energies. Third, the balance of overall dose contribution throughout the breast tissue is realized by automatically selecting anchor points and applying centrality correction. The proposed method was tested on the validation dataset. Non-parametric equivalence test was performed for plan quality metrics using one-sided Wilcoxon Signed-Rank test. Results: For validation, the auto-planning system suggested same energy choices as clinical-plans in 19 out of 20 cases. The mean (standard deviation, SD) of percent target volume covered by 100% prescription dose was 82.5% (4.2%) for auto-plans, and 79.3% (4.8%) for clinical-plans (p > 0.999). Mean (SD) volume receiving 105% Rx were 95.2 cc (90.7 cc) for auto-plans and 83.9 cc (87.2 cc) for clinical-plans (p = 0.108). Optimization time for auto-plan was <20 s while clinical manual planning takes between 30 min and 4 h. Conclusions: We developed an automatic treatment planning system that generates WBRT plans with optimal energy selection, clinically comparable plan quality, and significant reduction in planning time, allowing for near-real-time planning.Item Open Access Developing a biomechanical model-based elasticity imaging method for assessing hormone receptor positive breast cancer treatment-related myocardial stiffness changes.(Journal of medical imaging (Bellingham, Wash.), 2021-09) Miller, Caroline E; Jordan, Jennifer H; Thomas, Alexandra; Weis, Jared APurpose: Assessing cardiotoxicity as a result of breast cancer therapeutics is increasingly important as breast cancer diagnoses are trending younger and overall survival is increasing. With evidence showing that prevention of cardiotoxicity plays a significant role in increasing overall survival, there is an unmet need for accurate non-invasive methods to assess cardiac injury due to cancer therapies. Current clinical methods are too coarse and emerging research methods have not yet achieved clinical implementation. Approach: As a proof of concept, we examine myocardial elasticity imaging in the setting of premenopausal women diagnosed with hormone receptor positive (HR-positive) breast cancer undergoing severe estrogen depletion, as cardiovascular injury from early estrogen depletion is well-established. We evaluate the ability of our model-based cardiac elasticity imaging analysis method to indicate subclinical cancer therapy-related cardiac decline by examining differences in the change in cardiac elasticity over time in two cohorts of premenopausal women either undergoing severe estrogen depletion for HR-positive breast cancer or triple negative breast cancer patients as comparators. Results: Our method was capable of producing functional mechanical elasticity maps of the left ventricle (LV). Using these elasticity maps, we show significant differences in cardiac mechanical elasticity in the HR-positive breast cancer cohort compared to the comparator cohort. Conclusions: We present our methodology to assess the mechanical stiffness of the LV by interrogating cardiac magnetic resonance images within a computational biomechanical model. Our preliminary study suggests the potential of this method for examining cardiac tissue mechanical stiffness properties as an early indicator of cardiac decline.Item Open Access Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.(J Biol Chem, 2017-01-13) Alexander, Peter B; Chen, Rui; Gong, Chang; Yuan, Lifeng; Jasper, Jeff S; Ding, Yi; Markowitz, Geoffrey J; Yang, Pengyuan; Xu, Xin; McDonnell, Donald P; Song, Erwei; Wang, Xiao-FanTargeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.Item Open Access Dual-emissive, oxygen-sensing boron nanoparticles quantify oxygen consumption rate in breast cancer cells.(Journal of biomedical optics, 2020-11) Rickard, Ashlyn G; Zhuang, Meng; DeRosa, Christopher A; Zhang, Xiaojie; Dewhirst, Mark W; Fraser, Cassandra L; Palmer, Gregory MSignificance
Decreasing the oxygen consumption rate (OCR) of tumor cells is a powerful method for ameliorating tumor hypoxia. However, quantifying the change in OCR is challenging in complex experimental systems.Aim
We present a method for quantifying the OCR of two tumor cell lines using oxygen-sensitive dual-emissive boron nanoparticles (BNPs). We hypothesize that our BNP results are equivalent to the standard Seahorse assay.Approach
We quantified the spectral emissions of the BNP and accounted for external oxygen diffusion to quantify OCR over 24 h. The BNP-computed OCR of two breast cancer cell lines, E0771 and 4T07, were compared with their respective Seahorse assays. Both cell lines were also irradiated to quantify radiation-induced changes in the OCR.Results
Using a Bland-Altman analysis, our BNPs OCR was equivalent to the standard Seahorse assay. Moreover, in an additional experiment in which we irradiated the cells at their 50% survival fraction, the BNPs were sensitive enough to quantify 24% reduction in OCR after irradiation.Conclusions
Our results conclude that the BNPs are a viable alternative to the Seahorse assay for quantifying the OCR in cells. The Bland-Altman analysis showed that these two methods result in equivalent OCR measurements. Future studies will extend the OCR measurements to complex systems including 3D cultures and in vivo models, in which OCR measurements cannot currently be made.Item Open Access Experience and Perceptions of a Family Health History Risk Assessment Tool among Multi-Ethnic Asian Breast Cancer Patients.(J Pers Med, 2021-10-19) Yoon, Sungwon; Goh, Hendra; Fung, Si Ming; Tang, Shihui; Matchar, David; Ginsburg, Geoffrey S; Orlando, Lori A; Ngeow, Joanne; Wu, Rebekah RyanneA family health history-based risk assessment is particularly valuable for guiding cancer screening and treatment strategies, yet an optimal implementation depends upon end-users' values and needs. This is not only true prior to disease development, but also for those already affected. The aim of this study is to explore perceptions of the value of knowing one's family health history (FHH)-based risk, experience using a patient-facing FHH tool and the potential of the tool for wider implementation. Twenty multi-ethnic Asian patients undergoing breast cancer treatment in Singapore completed an FHH-based risk assessment. Semi-structured one-on-one interviews were conducted and data were thematically analyzed. All participants were female and slightly more than half were Chinese. The acceptance and usage of an FHH risk assessment tool for cancers and its broader implementation was affected by a perceived importance of personal control over early detection, patient concerns of anxiety for themselves and their families due to risk results, concerns for genetic discrimination, adequacy of follow-up care plans and Asian cultural beliefs toward disease and dying. This study uniquely sheds light on the factors affecting Asian breast cancer patients' perceptions about undergoing an FHH-based risk assessment, which should inform steps for a broader implementation in Asian healthcare systems.Item Open Access Goal-Driven Beam Setting Optimization for Whole-Breast Radiation Therapy.(Technology in cancer research & treatment, 2019-01) Wang, Wentao; Sheng, Yang; Yoo, Sua; Blitzblau, Rachel C; Yin, Fang-Fang; Wu, Q JackiePURPOSE:To develop an automated optimization program to generate optimal beam settings for whole-breast radiation therapy driven by clinically oriented goals. MATERIALS AND METHODS:Forty patients were retrospectively included in this study. Each patient's planning images, contoured structures of planning target volumes, organs-at-risk, and breast wires were used to optimize for patient-specific-beam settings. Two beam geometries were available tangential beams only and tangential plus supraclavicular beams. Beam parameters included isocenter position, gantry, collimator, couch angles, and multileaf collimator shape. A geometry-based goal function was defined to determine such beam parameters to minimize out-of-field target volume and in-field ipsilateral lung volume. For each geometry, the weighting in the goal function was trained with 10 plans and tested on 10 additional plans. For each query patient, the optimal beam setting was searched for different gantry-isocenter pairs. Optimal fluence maps were generated by an in-house automatic fluence optimization program for target coverage and homogeneous dose distribution, and dose calculation was performed in Eclipse. Automatically generated plans were compared with manually generated plans for target coverage and lung and heart sparing. RESULTS:The program successfully produced a set of beam parameters for every patient. Beam optimization time ranged from 10 to 120 s. The automatic plans had overall comparable plan quality to manually generated plans. For all testing cases, the mean target V95% was 91.0% for the automatic plans and 88.5% for manually generated plans. The mean ipsilateral lung V20Gy was lower for the automatic plans (15.2% vs 17.9%). The heart mean dose, maximum dose of the body, and conformity index were all comparable. CONCLUSION:We developed an automated goal-driven beam setting optimization program for whole-breast radiation therapy. It provides clinically relevant solutions based on previous clinical practice as well as patient specific anatomy on a substantially faster time frame.Item Open Access m6A regulates breast cancer proliferation and migration through stage-dependent changes in Epithelial to Mesenchymal Transition gene expression.(Frontiers in oncology, 2023-01) Dorgham, Mohammed G; Elliott, Brittany A; Holley, Christopher L; Mansfield, Kyle DWhile many factors have been implicated in breast cancer progression, effective treatments are still lacking. In recent years, it has become clear that posttranscriptional regulation plays a key role in the aberrant gene expression underlying malignancy and metastasis. For example, the mRNA modification N6-methyladenosine (m6A) is involved in numerous post-transcriptional regulation processes and has been implicated in many cancer types, including breast cancer. Despite intense study, even within a single type of cancer, there is little consensus, and often conflicting results, as to the role of m6A, suggesting other factors must influence the process. The goal of this study was to determine if the effects of m6A manipulation on proliferation and migration differed based on the stage of disease progression. Using the MCF10 model of breast cancer, we reduced m6A levels by targeting METTL3, the main cellular m6A RNA methyltransferase. Knocking down Mettl3 at different stages of breast cancer progression indeed shows unique effects at each stage. The early-stage breast cancer line showed a more proliferative phenotype with the knockdown of Mettl3 while the transformed breast cancer line showed a more migratory phenotype. Interestingly, the metastasized breast cancer cell line showed almost no effect on phenotype with the knockdown of Mettl3. Furthermore, transcriptome wide analysis revealed EMT as the probable pathway influencing the phenotypic changes. The results of this study may begin to address the controversy of m6A's role in cancer and suggest that m6A may have a dynamic role in cancer that depends on the stage of progression.Item Open Access Micro-CT imaging of breast tumors in rodents using a liposomal, nanoparticle contrast agent.(Int J Nanomedicine, 2009) Samei, Ehsan; Saunders, Robert S; Badea, Cristian T; Ghaghada, Ketan B; Hedlund, Laurence W; Qi, Yi; Yuan, Hong; Bentley, Rex C; Mukundan, SrinivasanA long circulating liposomal, nanoscale blood pool agent encapsulating traditional iodinated contrast agent (65 mg I/mL) was used for micro-computed tomography (CT) imaging of rats implanted with R3230AC mammary carcinoma. Three-dimensional vascular architecture of tumors was imaged at 100-micron isotropic resolution. The image data showed good qualitative correlation with pathologic findings. The approach holds promise for studying tumor angiogenesis and for evaluating anti-angiogenesis therapies.Item Open Access Nodal Response to Neoadjuvant Chemotherapy Predicts Receipt of Radiation Therapy after Breast Cancer Diagnosis.(International journal of radiation oncology, biology, physics, 2019-10-31) Fayanju, Oluwadamilola M; Ren, Yi; Suneja, Gita; Thomas, Samantha M; Greenup, Rachel A; Plichta, Jennifer K; Rosenberger, Laura H; Force, Jeremy; Hyslop, Terry; Hwang, E ShelleyBACKGROUND:Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with improved overall survival (OS) in breast-cancer patients, but it is unclear how post-NACT response influences radiotherapy administration in patients presenting with node-positive disease. We sought to determine whether nodal pCR is associated with likelihood of receiving nodal radiation and whether radiotherapy among patients experiencing nodal pCR is associated with improved OS. METHODS:cN1 female breast cancer patients diagnosed 2010-2015 who were ypN0 (i.e., nodal pCR, n=12,341) or ypN1 (i.e., residual disease, n=13,668) post-NACT were identified in the National Cancer Database. Multivariate logistic regression was used to identify factors associated with receiving radiotherapy. Cox proportional hazards modeling was used to estimate the association between radiotherapy and adjusted OS. RESULTS:26,009 patients were included. 43.9% (n=5,423) of ypN0 and 55.3% (n=7,556) of ypN1 patients received nodal radiation. Rates of nodal radiation remained the same over time among ypN0 patients (trend test p=0.29) but increased among ypN1 patients from 49% in 2010 to 59% in 2015 (trend test p<0.001). After adjusting for covariates, nodal pCR (vs no stage change) was associated with decreased likelihood of nodal radiation after mastectomy (∼20% decrease) and lumpectomy (∼30% decrease, both p<0.01). After mastectomy, nodal (vs no) radiation conferred no significant survival benefit in ypN0 patients but approached significance for ypN1 patients (hazard ratio [HR] 0.83, 95% CI 0.69-0.99, p=0.04, overall p-value=0.11). After lumpectomy, nodal radiation was associated with improved adjusted OS for ypN0 (HR 0.38, 95% CI 0.22-0.66) and ypN1 patients (HR 0.44, 95% CI 0.30-0.66, both p<0.001), but this improvement was not significantly greater than that associated with breast-only radiation. CONCLUSIONS:ypN0 patients were less likely to receive nodal radiation than ypN1 patients, suggesting that selective omission already occurs and, in the context of limited survival data, could potentially be appropriate for select patients.Item Open Access Perspectives on Inflammatory Breast Cancer (IBC) Research, Clinical Management and Community Engagement from the Duke IBC Consortium.(Journal of Cancer, 2019-01) Devi, Gayathri R; Hough, Holly; Barrett, Nadine; Cristofanilli, Massimo; Overmoyer, Beth; Spector, Neil; Ueno, Naoto T; Woodward, Wendy; Kirkpatrick, John; Vincent, Benjamin; Williams, Kevin P; Finley, Charlotte; Duff, Brandi; Worthy, Valarie; McCall, Shannon; Hollister, Beth A; Palmer, Greg; Force, Jeremy; Westbrook, Kelly; Fayanju, Oluwadamilola; Suneja, Gita; Dent, Susan F; Hwang, E Shelley; Patierno, Steven R; Marcom, P KellyInflammatory breast cancer (IBC) is an understudied and aggressive form of breast cancer with a poor prognosis, accounting for 2-6% of new breast cancer diagnoses but 10% of all breast cancer-related deaths in the United States. Currently there are no therapeutic regimens developed specifically for IBC, and it is critical to recognize that all aspects of treating IBC - including staging, diagnosis, and therapy - are vastly different than other breast cancers. In December 2014, under the umbrella of an interdisciplinary initiative supported by the Duke School of Medicine, researchers, clinicians, research administrators, and patient advocates formed the Duke Consortium for IBC to address the needs of patients in North Carolina (an ethnically and economically diverse state with 100 counties) and across the Southeastern United States. The primary goal of this group is to translate research into action and improve both awareness and patient care through collaborations with local, national and international IBC programs. The consortium held its inaugural meeting on Feb 28, 2018, which also marked Rare Disease Day and convened national research experts, clinicians, patients, advocates, government representatives, foundation leaders, staff, and trainees. The meeting focused on new developments and challenges in the clinical management of IBC, research challenges and opportunities, and an interactive session to garner input from patients, advocates, and community partners that would inform a strategic plan toward continuing improvements in IBC patient care, research, and education.Item Open Access Pleiotropic MLLT10 variation confers risk of meningioma and estrogen-mediated cancers.(Neuro-oncology advances, 2022-01) Walsh, Kyle M; Zhang, Chenan; Calvocoressi, Lisa; Hansen, Helen M; Berchuck, Andrew; Schildkraut, Joellen M; Bondy, Melissa L; Wrensch, Margaret; Wiemels, Joseph L; Claus, Elizabeth BBackground
Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ovarian cancers, raising the possibility of genetic pleiotropy.Methods
We performed imputation-based fine-mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28 108 cases, 22 209 controls), and ovarian cancer (25 509 cases, 40 941 controls). Analyses were stratified by sex (meningioma), estrogen receptor (ER) status (breast), and histotype (ovarian), then combined using subset-based meta-analysis in ASSET. Lead variants were assessed for association with additional traits in UK Biobank to identify potential effect-mediators.Results
Two-sided subset-based meta-analysis identified rs7084454, an expression quantitative trait locus (eQTL) near the MLLT10 promoter, as lead variant (5.7 × 10-14). The minor allele was associated with increased risk of meningioma in females (odds ratio (OR) = 1.42, 95% Confidence Interval (95%CI):1.20-1.69), but not males (OR = 1.19, 95%CI: 0.91-1.57). It was positively associated with ovarian (OR = 1.09, 95%CI:1.06-1.12) and ER+ breast (OR = 1.05, 95%CI: 1.02-1.08) cancers, and negatively associated with ER- breast cancer (OR = 0.91, 95%CI: 0.86-0.96). It was also associated with several adiposity traits (P < 5.0 × 10-8), but adjusting for body mass index did not attenuate its association with meningioma. MLLT10 and ESR1 expression were positively correlated in normal meninges (P = .058) and meningioma tumors (P = .0065).Conclusions
We identify a MLLT10 eQTL positively associated with risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, and implicate a potential estrogenic mechanism underlying this pleiotropy.Item Open Access Strategies to Prevent Cardiovascular Toxicity in Breast Cancer: Is It Ready for Primetime?(Journal of clinical medicine, 2020-03-25) Kikuchi, Robin; Shah, Nishant P; Dent, Susan FCardio-oncology is an emerging field tasked with identifying and treating cancer therapy related cardiac dysfunction (e.g., cytotoxic agents, immunotherapies, radiation, and hormone therapies) and optimizing the cardiovascular health of cancer patients exposed to these agents. Novel cancer therapies have led to significant improvements in clinical outcomes for breast cancer patients. In this article, we review the current literature on assessing cardiovascular risk of breast cancer therapies and discuss strategies (including pharmacological and lifestyle interventions) to prevent cardiovascular toxicity.