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Grant Details

Grant Number: 1R01CA231925-01A1 Interpret this number
Primary Investigator: Singh, Seema
Organization: University Of South Alabama
Project Title: Impact of Social Factors on Breast Cancer Biology in African-American Women
Fiscal Year: 2019
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Abstract

ABSTRACT African American (AA) women are more likely to be diagnosed at an early age with breast cancer (BC), have aggressive disease and experience greater mortality, compared to their Caucasian American (CA) counterparts. Socioeconomic status (SES) and social stress have long been believed to be the prime cause of such health disparities; however, it is not yet well understood how these social factors are translated into increased cancer risk, aggressive tumor-subtypes, and poor clinical outcomes. Demographic data suggest that AA women encounter more socioeconomic difficulties than CA women and social stressors impact human biology through epigenomic modifications of gene functions. MicroRNAs, which are important epigenetic modulators of gene expression and key players in human biology and disease, are known to be regulated by stress hormones/cytokines and exhibit differential expression in socially disadvantaged population. Along these lines, our published and preliminary studies have identified increased serum levels of inflammatory cytokines and stress hormones (resistin, IL6, leptin, and cortisol), and certain microRNAs (miR-511, miR-27a, and miR-33a) in AA women (with or without BC). We have also observed that treatment of BC cells and macrophages with resistin, IL6, leptin, and cortisol leads to an upregulation of miR-511, miR-27a, and miR-33a, promotes growth and malignant behavior of BC cells, and induces M2 polarization of macrophages. These compelling findings build a strong scientific premise for this project and support our hypothesis that socioeconomic hardships promote chronic inflammation and stress leading to altered serum levels of hormones and cytokines (such as resistin, IL6, leptin, and cortisol), which in turn, modulate the expression of immune-suppressive and tumor- promoting miRNAs, eventually contributing to BC pathogenesis. In four specific aims, we propose to determine global changes in circulating microRNAs in serum of AA and CA women (with or without BC) and establish their correlation with SES (low/moderate/high) (Aim 1); analyze levels of resistin, IL6, leptin, and cortisol in serum, and study their association with SES and serum miRNAs (Aim 2); examine regulation of miRNAs by resistin, IL6, leptin, and cortisol and delineate the underlying mechanisms (Aim 3); and establish the pathobiological significance of differentially-expressed miRNAs (Aim 4). Together, these studies will establish the functional association between socioeconomic health determinants and breast tumor biology, and support the role of miRNAs as epigenomic modifiers that link the social stress to biological phenotypes.

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Publications

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope.
Authors: Saranyutanon S. , Srivastava S.K. , Pai S. , Singh S. , Singh A.P. .
Source: Cancers, 2019-12-23; 12(1), .
EPub date: 2019-12-23.
PMID: 31877956
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Looking at cancer health disparities without the colored lenses.
Authors: Khan M.A. , Patel G.K. , Srivastava S.K. , Carter J.E. , Pierce J.Y. , Rocconi R.P. , Singh S. , Singh A.P. .
Source: Cancer health disparities, 2019; 3, p. e1-e9.
EPub date: 2019-08-19.
PMID: 31440743
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ETV4 Facilitates Cell-Cycle Progression in Pancreatic Cells through Transcriptional Regulation of Cyclin D1.
Authors: Tyagi N. , Deshmukh S.K. , Srivastava S.K. , Azim S. , Ahmad A. , Al-Ghadhban A. , Singh A.P. , Carter J.E. , Wang B. , Singh S. .
Source: Molecular cancer research : MCR, 2018 02; 16(2), p. 187-196.
EPub date: 2017-11-08.
PMID: 29117940
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Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings.
Authors: Deshmukh S.K. , Srivastava S.K. , Tyagi N. , Ahmad A. , Singh A.P. , Ghadhban A.A.L. , Dyess D.L. , Carter J.E. , Dugger K. , Singh S. .
Source: Carcinogenesis, 2017-08-01; 38(8), p. 757-765.
PMID: 28430867
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Epigenetic basis of cancer health disparities: Looking beyond genetic differences.
Authors: Ahmad A. , Azim S. , Zubair H. , Khan M.A. , Singh S. , Carter J.E. , Rocconi R.P. , Singh A.P. .
Source: Biochimica et biophysica acta. Reviews on cancer, 2017 Aug; 1868(1), p. 16-28.
EPub date: 2017-01-17.
PMID: 28108348
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Resistin potentiates chemoresistance and stemness of breast cancer cells: Implications for racially disparate therapeutic outcomes.
Authors: Deshmukh S.K. , Srivastava S.K. , Zubair H. , Bhardwaj A. , Tyagi N. , Al-Ghadhban A. , Singh A.P. , Dyess D.L. , Carter J.E. , Singh S. .
Source: Cancer letters, 2017-06-28; 396, p. 21-29.
EPub date: 2017-03-14.
PMID: 28302531
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Comparative analysis of the relative potential of silver, Zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis.
Authors: Tyagi N. , Srivastava S.K. , Arora S. , Omar Y. , Ijaz Z.M. , Al-Ghadhban A. , Deshmukh S.K. , Carter J.E. , Singh A.P. , Singh S. .
Source: Cancer letters, 2016-12-01; 383(1), p. 53-61.
EPub date: 2016-09-28.
PMID: 27693632
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p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling.
Authors: Tyagi N. , Marimuthu S. , Bhardwaj A. , Deshmukh S.K. , Srivastava S.K. , Singh A.P. , McClellan S. , Carter J.E. , Singh S. .
Source: Cancer letters, 2016-01-28; 370(2), p. 260-7.
EPub date: 2015-11-03.
PMID: 26546043
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Silver nanoparticles protect human keratinocytes against UVB radiation-induced DNA damage and apoptosis: potential for prevention of skin carcinogenesis.
Authors: Arora S. , Tyagi N. , Bhardwaj A. , Rusu L. , Palanki R. , Vig K. , Singh S.R. , Singh A.P. , Palanki S. , Miller M.E. , et al. .
Source: Nanomedicine : nanotechnology, biology, and medicine, 2015 Jul; 11(5), p. 1265-75.
EPub date: 2015-03-21.
PMID: 25804413
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Insights into the Role of microRNAs in Pancreatic Cancer Pathogenesis: Potential for Diagnosis, Prognosis, and Therapy.
Authors: Khan M.A. , Zubair H. , Srivastava S.K. , Singh S. , Singh A.P. .
Source: Advances in experimental medicine and biology, 2015; 889, p. 71-87.
PMID: 26658997
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MicroRNAs in pancreatic malignancy: progress and promises.
Authors: Srivastava S.K. , Arora S. , Singh S. , Bhardwaj A. , Averett C. , Singh A.P. .
Source: Cancer letters, 2014-06-01; 347(2), p. 167-74.
EPub date: 2014-02-20.
PMID: 24561061
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Cancer "stemness"- regulating microRNAs: role, mechanisms and therapeutic potential.
Authors: Bhardwaj A. , Arora S. , Prajapati V.K. , Singh S. , Singh A.P. .
Source: Current drug targets, 2013 Sep; 14(10), p. 1175-84.
PMID: 23834145
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