title: Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression.
abstract: Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment.
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, Granada, Spain. Biosanitary Institute of Granada (ibs. GRANADA), University of Granada, Granada, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Picon-Ruiz
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Chendong
authors.initials: C
authors.lastname: Pan
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Katherine
authors.initials: K
authors.lastname: Drews-Elger
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Kibeom
authors.initials: K
authors.lastname: Jang
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Donald and Sheila Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Besser
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Donald and Sheila Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Dekuang
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, Granada, Spain. Biosanitary Institute of Granada (ibs. GRANADA), University of Granada, Granada, Spain.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Morata-Tarifa
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Minsoon
authors.initials: M
authors.lastname: Kim
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Tan A
authors.initials: TA
authors.lastname: Ince
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Azzam
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Donald and Sheila Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Wander
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Burcu
authors.initials: B
authors.lastname: Ergonul
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Biomedical Nanoscience Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Ram H
authors.initials: RH
authors.lastname: Datar
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Biomedical Nanoscience Institute, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cote
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida. Geriatric Research, Education and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Howard
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Dorraya
authors.initials: D
authors.lastname: El-Ashry
authors.affiliation: Biosanitary Institute of Granada (ibs. GRANADA), University of Granada, Granada, Spain. Department of Surgery, San Cecilio University Hospital, University of Granada, Granada, Spain. Department of Mammary Pathology, San Cecilio University Hospital, University of Granada, Granada, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Torné-Poyatos
authors.affiliation: Biopathology and Medicine Regenerative Institute (IBIMER), University of Granada, Granada, Spain. Biosanitary Institute of Granada (ibs. GRANADA), University of Granada, Granada, Spain. Department of Human Anatomy and Embryology, University of Granada, Granada, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Marchal
authors.affiliation: Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida. Donald and Sheila Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida. Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. jslingerland@med.miami.edu.
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Slingerland
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D009765:Obesity / Q000150:complications*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D019061:src-Family Kinases