Melissa Davis
University of Georgia
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Featured researches published by Melissa Davis.
Oncotarget | 2016
Honghe Wang; Wei Liu; ShaNekkia Black; Omari Turner; Juliet M. Daniel; Windy Dean-Colomb; Qinghua P. He; Melissa Davis; Clayton Yates
Kaiso, a member of the BTB/POZ zinc finger protein family, functions as a transcriptional repressor by binding to sequence-specific Kaiso binding sites or to methyl-CpG dinucleotides. Previously, we demonstrated that Kaiso overexpression and nuclear localization correlated with the progression of prostate cancer (PCa). Therefore, our objective was to explore the molecular mechanisms underlying Kaiso-mediated PCa progression. Comparative analysis of miRNA arrays revealed that 13 miRNAs were significantly altered (> 1.5 fold, p < 0.05) in sh-Kaiso PC-3 compared to sh-Scr control cells. Real-time PCR validated that three miRNAs (9, 31, 636) were increased in sh-Kaiso cells similar to cells treated with 5-aza-2′-deoxycytidine. miR-31 expression negatively correlated with Kaiso expression and with methylation of the miR-31 promoter in a panel of PCa cell lines. ChIP assays revealed that Kaiso binds directly to the miR-31 promoter in a methylation-dependent manner. Over-expression of miR-31 decreased cell proliferation, migration and invasiveness of PC-3 cells, whereas cells transfected with anti-miR-31 restored proliferation, migration and invasiveness of sh-Kaiso PC-3 cells. In PCa patients, Kaiso high/miR-31 low expression correlated with worse overall survival relative to each marker individually. In conclusion, these results demonstrate that Kaiso promotes cell migration and invasiveness through regulation of miR-31 expression.
Cancer Letters | 2016
Jacqueline Jones; Angana Mukherjee; Balasubramanyam Karanam; Melissa Davis; Jesse Jaynes; Renee Reams; Windy Dean-Colomb; Clayton Yates
Kaiso, a bi-modal transcription factor, regulates gene expression, and is elevated in breast, prostate, and colon cancers. Depletion of Kaiso in other cancer types leads to a reduction in markers for the epithelial-mesenchymal transition (EMT) (Jones et al., 2014), however its clinical implications in pancreatic ductal adenocarcinoma (PDCA) have not been widely explored. PDCA is rarely detected at an early stage but is characterized by rapid progression and invasiveness. We now report the significance of the subcellular localization of Kaiso in PDCAs from African Americans. Kaiso expression is higher in the cytoplasm of invasive and metastatic pancreatic cancers. In males, cytoplasmic expression of Kaiso correlates with cancer grade and lymph node positivity. In male and female patients, cytoplasmic Kaiso expression correlates with invasiveness. Also, nuclear expression of Kaiso increases with increased invasiveness and lymph node positivity. Further, analysis of the largest PDCA dataset available on ONCOMINE shows that as Kaiso increases, there is an overall increase in Zeb1, which is the inverse for E-cadherin. Hence, these findings suggest a role for Kaiso in the progression of PDCAs, involving the EMT markers, E-cadherin and Zeb1.
Scientific Reports | 2017
Rupali Hire; Shalini Srivastava; Melissa Davis; Ananda Kumar Konreddy; Dulal Panda
Crocin, a component of saffron spice, is known to have an anticancer activity. However, the targets of crocin are not known. In this study, crocin was found to inhibit the proliferation of HCC70, HCC1806, HeLa and CCD1059sk cells by targeting microtubules. Crocin depolymerized both the interphase and mitotic microtubules of different cancer cells, inhibited mitosis and induced multipolar spindle formation in these cells. In vitro, crocin inhibited the assembly of pure tubulin as well as the assembly of microtubule-associated protein rich tubulin. Electron microscopic analysis showed that crocin inhibited microtubule assembly while it induced aggregation of tubulin at higher concentrations. Crocin co-eluted with tubulin suggesting that it binds to tubulin. Vinblastine inhibited the binding of crocin to tubulin while podophyllotoxin did not inhibit the crocin binding indicating that crocin binds at the vinblastine site on tubulin. The results suggested that crocin inhibited cell proliferation mainly by disrupting the microtubule network.
PLOS ONE | 2015
Melissa Davis; Andrea Walens; Rupali Hire; Kauthar Mumin; Andrea M. Brown; De Juana Ford; Elizabeth W. Howerth; Michele Monteil
The Atypical ChemoKine Receptor 1 (ACKR1) gene, better known as Duffy Antigen Receptor for Chemokines (DARC or Duffy), is responsible for the Duffy Blood Group and plays a major role in regulating the circulating homeostatic levels of pro-inflammatory chemokines. Previous studies have shown that one common variant, the Duffy Null (Fy-) allele that is specific to African Ancestry groups, completely removes expression of the gene on erythrocytes; however, these individuals retain endothelial expression. Additional alleles are associated with a myriad of clinical outcomes related to immune responses and inflammation. In addition to allele variants, there are two distinct transcript isoforms of DARC which are expressed from separate promoters, and very little is known about the distinct transcriptional regulation or the distinct functionality of these protein isoforms. Our objective was to determine if the African specific Fy- allele alters the expression pattern of DARC isoforms and therefore could potentially result in a unique signature of the gene products, commonly referred to as antigens. Our work is the first to establish that there is expression of DARC on lymphoblasts. Our data indicates that people of African ancestry have distinct relative levels of DARC isoforms expressed in these cells. We conclude that the expression of both isoforms in combination with alternate alleles yields multiple Duffy antigens in ancestry groups, depending upon the haplotypes across the gene. Importantly, we hypothesize that DARC isoform expression patterns will translate into ancestry-specific inflammatory responses that are correlated with the axis of pro-inflammatory chemokine levels and distinct isoform-specific interactions with these chemokines. Ultimately, this work will increase knowledge of biological mechanisms underlying disparate clinical outcomes of inflammatory-related diseases among ethnic and geographic ancestry groups.
International Journal of Environmental Research and Public Health | 2015
Anne Marie Zimeri; Sara Wagner Robb; Sayed M. Hassan; Rupali Hire; Melissa Davis
Breast cancer (BrCA) is the most common cancer affecting women around the world. However, it does not arise from the same causative agent among all women. Genetic markers have been associated with heritable or familial breast cancers, which may or may not be confounded by environmental factors, whereas sporadic breast cancer cases are more likely attributable to environmental exposures. Approximately 85% of women diagnosed with BrCA have no family history of the disease. Given this overwhelming bias, more plausible etiologic mechanisms should be investigated to accurately assess a woman’s risk of acquiring breast cancer. It is known that breast cancer risk is highly influenced by exogenous environmental cues altering cancer genes either by genotoxic mechanisms (DNA mutations) or otherwise. Risk assessment should comprehensively incorporate exposures to exogenous factors that are linked to a woman’s individual susceptibility. However, the exact role that some environmental agents (EA) play in tumor formation and/or cancer gene regulation is unclear. In this pilot project, we begin a multi-disciplinary approach to investigate the intersection of environmental exposures, cancer gene response, and BrCA risk. Here, we present data that show environmental exposure to heavy metals and PCBs in drinking water, heavy metal presence in plasma of nine patients with sporadic BrCA, and Toxic Release Inventory and geological data for a metal of concern, uranium, in Northeast Georgia.
Cancer Research | 2014
Andrea Walens; Brianna Bennett; Kauthar Mumin; Michael Lou; Rupali Hire; Michele Monteil; Melissa Davis
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA DARC (aka Duffy), a chemokine receptor, is expressed on erythrocytes and endothelial cells in blood vessels. It has been linked to inhibition of tumor metastasis, and to regulation of plasma levels of some cytokines. The Duffy null (Fy-) phenotype, in which DARC is not expressed on red blood cells, is especially prevalent among people of West African descent. Little is known about how the presence or absence of DARC expression may affect breast cancer metastases and overall survival among African-American and European- American women. Our lab is investigating whether Fy- phenotypes could be associated with increased BrCa metastasis by genotyping the Fy- (null and weak) alleles and assessing DARC gene expression in breast and lymphoblast cells using qPCR and Immunofluorescence (IF). There are two isoforms of DARC, each with the Fy- SNP located in the promoter of one and the 5’UTR of the other. Due to this SNP, it is plausible that the alternate isoform is specific to these cell types and may still be expressed. Here we present data from the preliminary stages of this project; including characterizing Duffy alleles in our cell line models. We have genotyped the 3 known DARC polymorphisms that result in Fy- (and weak) erythrocyte phenotypes in breast cancer and lymphoblast cell lines. Specifically, we validated the genotype of HAPMAP lines from Yoruba, African-American, and CEPH-European descent for the -541T>C point mutation Fy- allele (rs2814778). Our breast cancer (BrCa) lines are derived from tumors of varying molecular subtypes, isolated from African-American women. We show that these BrCa lines are homozygous for the Fy- allele and yet still express the DARC protein. The specific isoform expressed in these cells (DARC-2) may not be the same as used to phenotype the Fy- status in erythrocytes (DARC-1). This suggests that a Fy- genotype may have some tissue specific expression of DARC-2 in epithelial cells. As well, we show that the levels of expression of the two DARC isoforms vary and are distinct among ancestral groups. We also show expression on the RNA level for individuals who have the duffy null genotype, which will be further validated. In conclusion, we hypothesize that Fy- status, as determined in endothelial and erythrocytes in people of African descent, may remove the metastatic protection of DARC. Also, alternate expression of DARC-2 on epithelial cells may increase the rate of metastases in the African population. Currently, we are analyzing clinical samples (blood and breast tissues) from local breast cancer patients for Fy- status and will determine if this correlates with metastatic disease. In addition, biochemical experiments will be conducted to determine whether DARC-related chemokines are in higher prevalence in the Fy- patients, how the isoforms differ in their affinity to the chemokine ligands, and whether this is associated with specific breast cancer subtypes. Citation Format: Andrea Walens, Brianna Bennett, Kauthar Mumin, Michael Lou, Rupali Hire, Michele Monteil, Melissa Davis. Investigating correlations of DARC under-expression (Duffy null phenotypes) with increased breast cancer lymph node metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 132. doi:10.1158/1538-7445.AM2014-132
Cancer Epidemiology, Biomarkers & Prevention | 2017
Brittany D. Jenkins; Rachel N. Martini; Rupali Hire; Michele Monteil; Melissa Davis
The tumor microenvironment is a complex heterogeneous mixture of cancer cells, immune cells, and many other cell types contributing to a myriad of clinical outcomes for breast cancer (BrCa) patients. Chemokine receptors play an important role in maintaining the homeostasis of pro-inflammatory chemokines, and, in turn, help direct the migration of tumor-associated immune cells. Atypical chemokine receptors, such as the Atypical Chemokine Receptor 1 (ACKR1/DARC), act to sequester chemokine activity and control leukocyte migration during tumor-associated inflammation. ACKR1 is unique in that its associated gene carries a fixed mutation in African populations, causing the receptor to not be expressed on red blood cells as a response to endemic malaria in Africa. It is well-known that African-Americans in the United States tend to develop more aggressive BrCa subtypes, and as a result, experience more deaths per year from BrCa related causes. The purpose of this study is to characterize this disparity by investigating the distinct migration of tumor-associated immune cells between ACKR1 positive and negative tumors. We also wish to determine any correlations between ACKR1 and pro-inflammatory chemokines in various BrCa cell types. Using immunohistochemistry, relative expression levels were determined for ACKR1, cytotoxic T-cells, B-cells, dendritic cells, and macrophages in primary breast tumor samples. The levels of pro-inflammatory chemokines in circulation were determined using a Luminex immuno-assay on peripheral blood samples. Localization of ACKR1-associated chemokines was also investigated using immunofluorescence. Initial results from our study cohort indicate differential expression of immune cells on tumors expressing ACKR1, leading to a unique tumor microenvironment. We observed that ACKR1 positive tumors recruited B-cells and dendritic cells, whereas, ACKR1 negative tumors did not. Also, we found a positive correlation between ACKR1 expression in tumor tissue, and expression of CCL2 (MCP-1) and CXCL8 (IL-8) in the peripheral blood of our cancer patients. Finally, a strong co-localization of ACKR1 with CCL2 and CXCL8 was observed in cultured mammalian breast cancer cells. Overall, our pilot data suggests that the presence of ACKR1 on tumor cells changes the tumor microenvironment by recruiting a distinct subset of immune cells and pro-inflammatory chemokines to the area of inflammation. Citation Format: Brittany D. Jenkins, Rachel N. Martini, Rupali Hire, Michele A. Monteil, Melissa B. Davis. Distinct recruitment of tumor-associated immune cells correlates with increased pro-malignant chemokines in tumors expressing epithelial Atypical Chemokine Receptor 1 (ACKR1/DARC). [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B39.
Cancer Epidemiology, Biomarkers & Prevention | 2016
Kathryn Vollum; Rebekah Hutchins; Andrea M. Brown; Crystal Perez; Melissa Davis
Biological mechanisms that drive disparate incidences of aggressive breast cancer in women of African descent are still largely unknown. Despite the fact that White women are more often diagnosed with breast cancer, African-American women have more severe cases and more often die from their breast cancer. Certain clues surrounding the tumor behavior and aggressive nature of cancers in African Americans point to physiological contexts, perhaps even the immunological microenvironment of the cancer sites. We hypothesize that higher mortality rates, coupled with lower incidence of breast cancer in this population, compared to white women, suggests the susceptibility is not necessarily a predisposition to acquire cancer, but that once a malignant cell is formed, the physiological make-up of these individuals somehow drives the aggressive nature of the tumors. This would explain the poor prognosis and higher mortality rates. We further hypothesize that chronic pro-inflammatory status, and altered chemokine profiles in this population are a key to tumor progression disparities. These disparities are likely due to specific genetic differences. Specifically, we are investigating the role of the Atypical Chemokine Receptor (ACKR1/DARC) gene and its isoforms in influencing a woman9s chance of developing aggressive breast cancer subtypes. We aim to demonstrate that altered expression of DARC isoforms play a role in breast cancer severity and tumor aggression by regulating the infiltration of specific immune cell types into the tumor environment, by altering the levels of specific chemokines in the breast. We are investigating how the Duffy null allele, prevalent in all women of African descent, affects the ability of regulatory transcription factors to properly express ACKR1/DARC in epithelial and lymphoblast cells. GATA1 has been shown to regulate DARC in erythrocyte lineages; however, our previous findings indicate that DARC expression on epithelial (tumor) cells correlate with specific immune cell infiltrates. We have found that there are significant differences in epithelial Gata3 expression, correlating with DARC expression levels among ancestry groups. Using bioinformatics techniques, and ChIP-PCR we aim to define more precisely the transcription factors responsible for DARC isoform regulation. Specifically, by integrating expression data and interaction data with databases such as HEFalMp and identifying enrichment of biological processes with tools such as DAVID, we will identify additional candidate transcription factors by measuring associations of candidate gene expressions with DARC, we will define biological pathways related to immunological and inflammatory responses and test the ability of the highest priority candidate transcription factors to regulate DARC using siRNA techniques. Once we know what transcription factors are involved with epithelial expression of DARC, we can develop tools to further investigate how DARC plays a role in tumor progression in women of African descent. Citation Format: Kathryn Vollum, Rebekah Hutchins, Andrea M. Brown, Crystal Perez, Melissa B. Davis. Regulation of DARC isoforms among ancestry groups and associations with aggressive breast cancer subtypes. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B24.
Cancer Epidemiology, Biomarkers & Prevention | 2016
DeJuana Ford; Rupali Hire; Elizabeth W. Howerth; Briana Bennett; Krissean Lea; Jillian Hood; Melissa Davis
African-American women of all ages have higher breast cancer mortality rates than Caucasian women, despite lower breast cancer incidence among African-American women over 40. While differences in socioeconomic status and access to healthcare may play a role in this disparity, the disproportionately high occurrence of aggressive, triple-negative breast tumors in African-American women suggests a biological link between ancestry and breast cancer prognosis. Interestingly, both African ancestry and breast tumor aggressiveness are associated with distinct transcript and protein expression levels of Insulin-like growth factor-II (IGF-II) and its binding partner, Insulin-like growth factor binding protein 6 (IGFBP6), and we have previously observed higher levels of IGFBP6 transcript and protein expression in African-American and Yoruba (African) HapMap cell lines when compared to Amish cell lines. To gain a better understanding of potential mechanisms underlying these associations, we have investigated the expression and subcellular localization of these proteins and their transcripts using qPCR and immunofluorescence (IF). Our qPCR data indicate lower IGFBP6 transcript expression in breast cancer cells relative to normal cells, with lower transcript levels in the ER positive breast cancer cells than in triple negative cells. Conversely, our IF data revealed higher levels of IGFBP6 protein in ER positive breast cancer cells than in triple negative breast cancer cells, suggesting that breast tumor subtypes may be associated with unique patterns of transcript and protein regulation in these genes. We also observed a distinctive pattern of IGFBP6 subcellular localization in the triple-negative cells in which aggregates of this protein are localized at the edge of the nucleus, and co-localized with IGF-II. We hypothesize that IGF-II will be more dispersed throughout the nucleus following si-RNA knockdown of IGFBP6. Taken together, these data suggest the possibility of a subtype-specific IGF-II/IGFBP6 complex in triple negative breast cancer. Further studies will assess how this complex may promote tumor aggression in triple-negative breast tumors by inhibiting IGFBP69s IGF-independent, pro-apoptotic qualities within the nucleus and/or prolonging the half-life of IGF-II, thus promoting cancer cell growth. Citation Format: DeJuana Ford, Rupali Hire, Elizabeth Howerth, Briana Bennett, Krissean Lea, Jillian Hood, Melissa Davis. Triple-negative breast tumors exhibit distinctive patterns of expression and subcellular localization of Insulin-like Growth Factor Binding Protein 6. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B25.
Cancer immunology research | 2015
Melissa Davis; Michele Monteil; Rupali Hire; Elizabeth W. Howerth
The Duffy Antigen Receptor for Chemokines (DARC or ACKR1) gene regulates circulating levels of inflammatory chemokines and major alleles of the gene are associated with a myriad of clinical outcomes. There are two unique isoforms of DARC which are expressed from distinct separate promoters, but little is known about the expression or regulation of these isoforms. Using quantitative RT-PCR and Immunohistochemical studies of lymphoblastic cells from relevant ancestry groups, we recently found that a DARC polymorphism, the Duffy Null (Fy-) allele found almost exclusively in African ancestry groups, is associated with altered regulation of these isoforms. Our data indicates that people of African ancestry who carry the Fy- allele will have an altered expression pattern of DARC isoforms. Thusly, we investigated whether the Fy- allele is associated with distinct recruitment of monocytes to breast tumor epithelia, regulated by DARC modulated chemokines. This may translate into a suite of distinct inflammatory responses correlated with specific chemokine action and may explain the disparate clinical outcomes of breast cancer in this population. Citation Format: Melissa B. Davis, Michele Monteil, Rupali Hire, Elizabeth W. Howerth. The role of DARC in the immunological tumor microenvironment of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A63.