Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression

Manuel Picon-Ruiz; Chendong Pan; Katherine Drews-Elger; Kibeom Jang; Alexandra H Besser; Dekuang Zhao; Cynthia Morata-Tarifa; Minsoon Kim; Tan A Ince; Diana J Azzam; Seth A Wander; Bin Wang; Burcu Ergonul; Ram H Datar; Richard J Cote; Guy A Howard; Dorraya El-Ashry; Pablo Torné-Poyatos; Juan A Marchal; Joyce M Slingerland

doi:10.1158/0008-5472.CAN-15-0927

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Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression

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Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression

Manuel Picon-Ruiz, Chendong Pan, Katherine Drews-Elger, Kibeom Jang, Alexandra H Besser, Dekuang Zhao, Cynthia Morata-Tarifa, Minsoon Kim, Tan A Ince, Diana J Azzam, …

Cancer research (Chicago, Ill.), Vol.76(2), pp.491-504

2016-01-15

DOI: https://doi.org/10.1158/0008-5472.CAN-15-0927

PMID: 26744520

Abstract

Cytokines - metabolism

Signal Transduction

Obesity - complications

Humans

RNA, Messenger - genetics

Adipocytes - cytology

RNA, Messenger - metabolism

Disease Progression

Breast Neoplasms - metabolism

Animals

Breast Neoplasms - genetics

Transfection

Breast Neoplasms - pathology

Adipocytes - metabolism

src-Family Kinases - metabolism

Female

Mice

SOXB1 Transcription Factors

src-Family Kinases - genetics

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.108 Molecular & Cell Biology - Cancer & Development; 1.108.591 Cancer Stem Cells
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression
Creators: Manuel Picon-Ruiz - 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
Chendong Pan - Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
Katherine Drews-Elger - Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
Kibeom Jang - 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
Alexandra H Besser - 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
Dekuang Zhao - 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
Cynthia Morata-Tarifa - 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
Minsoon Kim - 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
Tan A Ince - 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
Diana J Azzam - Braman Family Breast Cancer Institute, UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
Seth A Wander - 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
Bin Wang - 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
Burcu Ergonul - 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
Ram H Datar - Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Biomedical Nanoscience Institute, University of Miami Miller School of Medicine, Miami, Florida
Richard J Cote - Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida. Biomedical Nanoscience Institute, University of Miami Miller School of Medicine, Miami, Florida
Guy A Howard - 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
Dorraya El-Ashry - 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
Pablo Torné-Poyatos - 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
Juan A Marchal - 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
Joyce M Slingerland - 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
Publication Details: Cancer research (Chicago, Ill.), Vol.76(2), pp.491-504
Publisher: United States
Academic Unit: Miller School of Medicine; UMMG Department of Pathology; UMMG Dept of Medicine - Geriatric Medicine and Palliative Care
Language: English
Resource Type: Journal article
PMID: 26744520
Record Identifier: 991031577553602976