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Title: Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression.
Authors: Picon-Ruiz, Manuel
Pan, Chendong
Drews-Elger, Katherine
Jang, Kibeom
Besser, Alexandra H
Zhao, Dekuang
Morata-Tarifa, Cynthia
Kim, Minsoon
Ince, Tan A
Azzam, Diana J
Wander, Seth A
Wang, Bin
Ergonul, Burcu
Datar, Ram H
Cote, Richard J
Howard, Guy A
El-Ashry, Dorraya
Torné-Poyatos, Pablo
Marchal, Juan A
Slingerland, Joyce M
metadata.dc.subject.mesh: Adipocytes
Breast Neoplasms
Disease Progression
RNA, Messenger
SOXB1 Transcription Factors
Signal Transduction
src-Family Kinases
Issue Date: 7-Jan-2016
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.
metadata.dc.identifier.doi: 10.1158/0008-5472.CAN-15-0927
Appears in Collections:Producción 2020

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