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Grant Details

Grant Number: 5R01CA231925-03 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: 2021


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.



Publications

Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation.
Authors: Deshmukh S.K. , Srivastava S.K. , Zubair H. , Khan M.A. , Singh A.P. , Singh S. .
Source: Cancers, 2021-09-07; 13(18), .
EPub date: 2021-09-07.
PMID: 34572725
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Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis.
Authors: Adebayo M. , Singh S. , Singh A.P. , Dasgupta S. .
Source: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021 06; 35(6), p. e21620.
PMID: 34048084
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Extracellular Nanovesicles: From Intercellular Messengers to Efficient Drug Delivery Systems.
Authors: Deshmukh S.K. , Khan M.A. , Singh S. , Singh A.P. .
Source: ACS omega, 2021-01-26; 6(3), p. 1773-1779.
EPub date: 2021-01-11.
PMID: 33521418
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Resistin: An inflammatory cytokine with multi-faceted roles in cancer.
Authors: Sudan S.K. , Deshmukh S.K. , Poosarla T. , Holliday N.P. , Dyess D.L. , Singh A.P. , Singh S. .
Source: Biochimica et biophysica acta. Reviews on cancer, 2020 12; 1874(2), p. 188419.
EPub date: 2020-08-19.
PMID: 32822824
Related Citations

Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research.
Authors: Saranyutanon S. , Deshmukh S.K. , Dasgupta S. , Pai S. , Singh S. , Singh A.P. .
Source: Cancers, 2020-09-17; 12(9), .
EPub date: 2020-09-17.
PMID: 32957478
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Exosomal Formulation Escalates Cellular Uptake of Honokiol Leading to the Enhancement of Its Antitumor Efficacy.
Authors: Kanchanapally R. , Khan M.A. , Deshmukh S.K. , Srivastava S.K. , Khushman M. , Singh S. , Singh A.P. .
Source: ACS omega, 2020-09-15; 5(36), p. 23299-23307.
EPub date: 2020-08-31.
PMID: 32954181
Related Citations

Comprehensive Analysis of Expression, Clinicopathological Association and Potential Prognostic Significance of RABs in Pancreatic Cancer.
Authors: Anand S. , Khan M.A. , Khushman M. , Dasgupta S. , Singh S. , Singh A.P. .
Source: International journal of molecular sciences, 2020-08-04; 21(15), .
EPub date: 2020-08-04.
PMID: 32759795
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Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy.
Authors: Zubair H. , Khan M.A. , Anand S. , Srivastava S.K. , Singh S. , Singh A.P. .
Source: Seminars in cancer biology, 2020-05-26; , .
EPub date: 2020-05-26.
PMID: 32470379
Related Citations

Dysregulation of metabolic enzymes in tumor and stromal cells: Role in oncogenesis and therapeutic opportunities.
Authors: Khan M.A. , Zubair H. , Anand S. , Srivastava S.K. , Singh S. , Singh A.P. .
Source: Cancer letters, 2020-03-31; 473, p. 176-185.
EPub date: 2020-01-07.
PMID: 31923436
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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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Inflammation, immunosuppressive microenvironment and breast cancer: opportunities for cancer prevention and therapy.
Authors: Deshmukh S.K. , Srivastava S.K. , Poosarla T. , Dyess D.L. , Holliday N.P. , Singh A.P. , Singh S. .
Source: Annals of translational medicine, 2019 Oct; 7(20), p. 593.
PMID: 31807574
Related Citations

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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