Browsing by Author "Cox, Mary L."

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    Breast Cancer Cell Detection and Characterization from Breast Milk-Derived Cells
    (American Association for Cancer Research, 2020-11) Bhat-Nakshatri, Poornima; Kumar, Brijesh; Simpson, Ed; Ludwig, Kandice K.; Cox, Mary L.; Gao, Hongyu; Liu, Yunlong; Nakshatri, Harikrishna; Surgery, School of Medicine
    Radiologic techniques remain the main method for early detection for breast cancer and are critical to achieve a favorable outcome from cancer. However, more sensitive detection methods to complement radiologic techniques are needed to enhance early detection and treatment strategies. Using our recently established culturing method that allows propagation of normal and cancerous breast epithelial cells of luminal origin, flow cytometry characterization, and genomic sequencing, we show that cancer cells can be detected in breast milk. Cells derived from milk from the breast with cancer were enriched for CD49f+/EpCAM-, CD44+/CD24-, and CD271+ cancer stem-like cells (CSC). These CSCs carried mutations within the cytoplasmic retention domain of HDAC6, stop/gain insertion in MORF4L1, and deletion mutations within SWI/SNF complex component SMARCC2. CSCs were sensitive to HDAC6 inhibitors, BET bromodomain inhibitors, and EZH2 inhibitors, as mutations in SWI/SNF complex components are known to increase sensitivity to these drugs. Among cells derived from breast milk of additional ten women not known to have breast cancer, two of them contained cells that were enriched for the CSC phenotype and carried mutations in NF1 or KMT2D, which are frequently mutated in breast cancer. Breast milk-derived cells with NF1 mutations also carried copy-number variations in CDKN2C, PTEN, and REL genes. The approach described here may enable rapid cancer cell characterization including driver mutation detection and therapeutic screening for pregnancy/postpartum breast cancers. Furthermore, this method can be developed as a surveillance or early detection tool for women at high risk for developing breast cancer. SIGNIFICANCE: These findings describe how a simple method for characterization of cancer cells in pregnancy and postpartum breast cancer can be exploited as a surveillance tool for women at risk of developing breast cancer.
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    Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast
    (AACR, 2019-05) Nakshatri, Harikrishna; Kumar, Brijesh; Burney, Heather; Cox, Mary L.; Jacobsen, Max; Sandusky, George; D’Souza-Schorey, Crislyn; Storniolo, Anna Maria; Biostatistics, School of Public Health
    Purpose: Genetic ancestry influences evolutionary pathways of cancers. However, whether ancestry influences cancer-induced field defects is unknown. The goal of this study was to utilize ancestry-mapped true normal breast tissues as controls to identify cancer-induced field defects in normal tissue adjacent to breast tumors (NATs) in women of African American (AA) and European (EA) ancestry. Experimental Design: A tissue microarray comprising breast tissues of ancestry-mapped 100 age-matched healthy women from the Komen Tissue Bank (KTB) at Indiana University (Indianapolis, IN) and tumor-NAT pairs from 100 women (300 samples total) was analyzed for the levels of ZEB1, an oncogenic transcription factor that is central to cell fate, mature luminal cell–enriched estrogen receptor alpha (ERα), GATA3, FOXA1, and for immune cell composition. Results: ZEB1+ cells, which were localized surrounding the ductal structures of the normal breast, were enriched in the KTB-normal of AA compared with KTB-normal of EA women. In contrast, in EA women, both NATs and tumors compared with KTB-normal contained higher levels of ZEB1+ cells. FOXA1 levels were lower in NATs compared with KTB-normal in AA but not in EA women. We also noted variations in the levels of GATA3, CD8+ T cells, PD1+ immune cells, and PDL1+ cell but not CD68+ macrophages in NATs of AA and EA women. ERα levels did not change in any of our analyses, pointing to the specificity of ancestry-dependent variations. Conclusions: Genetic ancestry–mapped tissues from healthy individuals are required for proper assessment and development of cancer-induced field defects as early cancer detection markers. This finding is significant in light of recent discoveries of influence of genetic ancestry on both normal biology and tumor evolution.
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    Moving Beyond "Risky Sex": Adolescent Sexual Resilience and Sexual Health in Young Adulthood
    (2011-08-23) Cox, Mary L.; Leech, Tamara G.J.; Gronfein, William Philip; Goldfinger, Johnny
    Sexual behaviors in adolescence establish the initial resources an individual carries into sexual relationships in adulthood. Current definitions of sexual resilience in adolescence are defined from a negative, risk-based lens. Resilience theory, more generally defined, considers both internal and external factors that promote adaptation to challenging situations. A direct, capital-based approach to studying adolescent sexual resilience has not been found in the extant literature and I propose that a new, more inclusive definition of sexual resilience in adolescence will be more strongly correlated with sexual health in young adults than the risk-based definition. This study creates mutually exclusive risk-based and capital-based measures of adolescent sexual resilience and examines their associations with sexual health outcomes in young adulthood. The data did not produce significant findings, yet descriptive results provide direction for future research. Research in this area is of critical importance as adolescence and young adulthood are unique life stages that involve significant development in areas that influence health, both short and long term. This research, through a proper resilience lens, will better guide adolescent sexual education to develop internal resources as well as provide adequate external resources for adolescents that promote better sexual health and agency outcomes in adulthood.
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    An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity
    (Springer Nature, 2021) Zhou, Zhuolong; Van der Jeught, Kevin; Fang, Yuanzhang; Yu, Tao; Li, Yujing; Ao, Zheng; Liu, Sheng; Zhang, Lu; Yang, Yang; Eyvani, Haniyeh; Cox, Mary L.; Wang, Xiyu; He, Xiaoming; Ji, Guang; Schneider, Bryan P.; Guo, Feng; Wan, Jun; Zhang, Xinna; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
    In breast cancer, genetic heterogeneity, the lack of actionable targets and immune evasion all contribute to the limited clinical response rates to immune checkpoint blockade therapy. Here, we report a high-throughput screen based on the functional interaction of mouse- or patient-derived breast tumour organoids and tumour-specific cytotoxic T cells for the identification of epigenetic inhibitors that promote antigen presentation and potentiate T-cell-mediated cytotoxicity. We show that the epigenetic inhibitors GSK-LSD1, CUDC-101 and BML-210, identified by the screen, display antitumour activities in orthotopic mammary tumours in mice, that they upregulate antigen presentation mediated by the major histocompatibility complex class I on breast tumour cells and that treatment with BML-210 substantially sensitized breast tumours to the inhibitor of the checkpoint programmed death-1. Standardized measurements of tumour-cell killing activity facilitated by tumour-organoid-T-cell screens may help with the identification of candidate immunotherapeutics for a range of cancers.
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    The role of the CTD phosphatase Rrt1 and post-translational modifications in regulation of RNA polymerase II
    (2014-07-07) Cox, Mary L.; Goebl, Mark G.; Mosley, Amber L.; Wek, Ronald C.
    RNA polymerase II (RNAPII) is regulated by multiple modifications to the C-terminal domain (CTD) of the largest subunit, Rpb1. This study has focused on the relationship between hyperphosphorylation of the CTD and RNAPII turnover and proteolytic degradation as well as post-translational modifications of the globular core of RNAPII. Following tandem affinity purification, western blot analysis showed that MG132 treated RTR1 ERG6 deletion yeast cells have accumulation of total RNAPII and in particular, the hyperphosphorylated form of the protein complex. In addition, proteomic studies using MuDPIT have revealed increased interaction between proteins of the ubiquitin-proteasome degradation system in the mutant MG132 treated yeast cells as well as potential ubiquitin and phosphorylation sites in RNAPII subunits, Rpb6 and Rpb1, respectively. A novel Rpb1 phosphorylation site, T1471-P, is located in the linker region between the CTD and globular domain of Rpb1 and will be the focus of future studies to determine biological significance of this post-translational modification.
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    Social Norms: Do We Love Norms Too Much?
    (Wiley, 2015-03) Bell, David C.; Cox, Mary L.; Department of Sociology, School of Liberal Arts
    Social norms are often cited as the cause of many social phenomena, especially as an explanation for prosocial family and relationship behaviors. And yet maybe we love the idea of social norms too much, as suggested by our failure to subject them to rigorous test. Compared to the detail in social norms theoretical orientations, there is very little detail in tests of normative theories. To provide guidance to researchers who invoke social norms as explanations, we catalog normative orientations that have been proposed to account for consistent patterns of action. We call on researchers to conduct tests of normative theories and the processes such theories assert.