Beige Adipocytes and African American Breast Tumors

米色脂肪细胞和非裔美国人乳腺肿瘤

• 批准号: 10202503
• 负责人: SHEHLA PERVIN
• 金额: $ 35.88万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202503
• 关键词: Adipocytes; Adipose tissue; African American; Aggressive behavior; Biological Process; Breast Cancer Cell; Breast Cancer cell line; Cells; Characteristics; Clinical; Coculture Techniques; Data; Development; Genetic; Growth; Human; IL-13Ralpha1; IL4 gene; Immunofluorescence Immunologic; Incidence; Infiltration; Interleukin-10; Interleukin-13; Mammary Neoplasms; Molecular; Mus; Nature; Outcome; Patients; Pharmacology; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Population; Property; Publishing; Regulation; Reporting; Role; Testing; Therapeutic Intervention; Time; Tissues; Tyrosine 3-Monooxygenase; VEGFA gene; Woman; Xenograft procedure; aldehyde dehydrogenase 1; aldehyde dehydrogenases; angiogenesis; arginase; base; cancer cell; cancer stem cell; cell type; cytokine; experimental study; improved; in vivo; macrophage; malignant breast neoplasm; mortality; neoplastic cell; neuregulin-4; new therapeutic target; novel; psoriasin; receptor for advanced glycation endproducts; small hairpin RNA; stem cell biomarkers; trait; triple-negative invasive breast carcinoma; tumor; tumor behavior; tumor growth; tumor microenvironment; tumor progression

African American (AA) women continue to suffer from high mortality rates from an aggressive form of breast cancer for which there is no treatment. Better understanding of the unique properties of AA tumor cells and the microenvironment that supports its growth might improve clinical outcomes. Macrophages are a lynchpin in tumor microenvironment regulation. Although high macrophage infiltration and increased angiogenesis are unique characteristics of AA breast tumors, mechanisms that support these biological processes remain poorly understood. We have recently demonstrated, for the first time that increase in beige/brown adipose phenotype promote development of xenografts from breast cancer cells. We have subsequently demonstrated that expression of beige markers is significantly increased in both xenografts obtained from AA triple- negative (TN) breast cancer cells as well as in AA TN breast tumors. Based on our published and preliminary data, we hypothesize that “cross-talk between tumor cells and beige adipocytes generates a unique microenvironment that promotes M2 macrophage phenotype and is conducive to high angiogenesis.” We will test our hypothesis with the following Specific Aims: Aim 1: Determine whether i) M2 macrophages increase beige adipose phenotype in breast cancer cells and ii) beige adipose cells crosstalk with tumor cells to increase aggressive behavior in AA TN breast tumors. Aim 2: Determine the molecular mechanisms by which beige adipocytes in AA breast tumors support and sustain M2 macrophage population. Aim 3: Determine whether Th2 cytokines in AA TN breast tumor microenvironment promote proliferation and commitment of bi-potent adipose precursors (AP) to beige lineage. Effect of depletion of tissue resident macrophages and tyrosine hydroxylase (TH) expressed in these macrophages, on beige adipose phenotype as well as tumor growth in-vivo will be analyzed. Co-culture experiments with adipocytes enriched in beige phenotype and AA TN breast cancer cells will be performed to elucidate mechanisms that support M2 macrophages/angiogenesis. We will examine the possible role of psoriasin, and beige adipose-enriched secretory factors Neuregulin 4 (Nrg4) and Meteorin- like (Metrnl) during the cross-talk between cancer cells and beige adipocytes. We will further analyze the role of psoriasin in promoting MCSC (ALDH+)-induced xenograft growth. Depletion/enrichment of breast tumor cells with adipose precursor PDGFRα cells will be examined for tumor growth, beige adipose/M2 markers and tumor growth. Increased understanding of detailed molecular mechanisms by which beige adipocytes sustain critical threshold of M2 macrophage population in tumor microenvironment and contribute to tumor progression may provide outstanding opportunity for therapeutic intervention for these aggressive AA TN breast tumors.

非裔美国人（AA）妇女因性侵而继续遭受高死亡率

项目成果

DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer.

• 发表时间: 2020-10
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Thalia Jimenez;Albert Barrios;A. Tucker;Javier Collazo;Nataly Arias;S. Fazel;Melanie Baker;M. Halim;T. Huynh;R. Singh;S. Pervin

Nicotine Synergizes with High-Fat Diet to Induce an Anti-Inflammatory Microenvironment to Promote Breast Tumor Growth.

• DOI: 10.1155/2020/5239419
• 发表时间: 2020
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Jimenez T;Friedman T;Vadgama J;Singh V;Tucker A;Collazo J;Sinha S;Hikim AS;Singh R;Pervin S
• 通讯作者: Pervin S

Human Brown Adipose Tissue and Metabolic Health: Potential for Therapeutic Avenues.

• DOI: 10.3390/cells10113030
• 发表时间: 2021-11-05
• 期刊: Cells
• 影响因子: 6
• 作者: Singh R;Barrios A;Dirakvand G;Pervin S
• 通讯作者: Pervin S