TY - JOUR
T1 - Interactions between adipocytes and breast cancer cells stimulate cytokine production and drive Src/Sox2/miR-302b-mediated malignant progression
AU - Picon-Ruiz, Manuel
AU - Pan, Chendong
AU - Drews-Elger, Katherine
AU - Jang, Kibeom
AU - Besser, Alexandra H.
AU - Zhao, Dekuang
AU - Morata-Tarifa, Cynthia
AU - Kim, Minsoon
AU - Ince, Tan A.
AU - Azzam, Diana J.
AU - Wander, Seth A.
AU - Wang, Bin
AU - Ergonul, Burcu
AU - Datar, Ram H.
AU - Cote, Richard J.
AU - Howard, Guy A.
AU - El-Ashry, Dorraya
AU - Torné-Poyatos, Pablo
AU - Marchal, Juan A.
AU - Slingerland, Joyce M.
N1 - Funding Information:
The authors thank their lab, M. Lippman, and M. Abreu for useful discussions. This work was supported by grants from the Breast Cancer Research Foundation (J.M. Slingerland and T.A. Ince) and Doris Duke Charitable Foundation (J.M. Slingerland, C. Pan, S.A. Wander, A.H. Besser, and B. Ergonul). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/1/15
Y1 - 2016/1/15
N2 - 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 humanderived 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 mammosphereforming 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 cytokineinduced 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.
AB - 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 humanderived 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 mammosphereforming 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 cytokineinduced 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.
UR - http://www.scopus.com/inward/record.url?scp=84955318898&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-0927
DO - 10.1158/0008-5472.CAN-15-0927
M3 - Article
C2 - 26744520
AN - SCOPUS:84955318898
SN - 0008-5472
VL - 76
SP - 491
EP - 504
JO - Cancer research
JF - Cancer research
IS - 2
ER -