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Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer

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Abstract

The tumor microenvironment plays a critical role in regulating breast tumor progression. Signaling between preadipocytes and breast cancer cells has been found to promote breast tumor formation and metastasis. Exosomes secreted from preadipocytes are important components of the cancer stem cell niche. Mouse preadipocytes (3T3L1) are treated with the natural antitumor compound shikonin (SK) and exosomes derived from mouse preadipocytes are co-cultured with MCF10DCIS cells. We examine how preadipocyte-derived exosomes can regulate early-stage breast cancer via regulating stem cell renewal, cell migration, and tumor formation. We identify a critical miR-140/SOX2/SOX9 axis that regulates differentiation, stemness, and migration in the tumor microenvironment. Next, we find that the natural antitumor compound SK can inhibit preadipocyte signaling inhibiting nearby ductal carcinoma in situ (DCIS) cells. Through co-culture experiments, we find that SK-treated preadipocytes secrete exosomes with high levels of miR-140, which can impact nearby DCIS cells through targeting SOX9 signaling. Finally, we find that preadipocyte-derived exosomes promote tumorigenesis in vivo, providing strong support for the importance of exosomal signaling in the tumor microenvironment. Our data also show that targeting the tumor microenvironment may assist in blocking tumor progression.

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Acknowledgments

This work was supported by Grants from the NCI R01 (Q.Z), the American Cancer Society (Q.Z.) and NCI 5F31CA183522 (G.E.).

Conflict of interest

All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Ramkishore Gernapudi, Yuan Yao, Yongshu Zhang, Benjamin Wolfson, Sanchita Roy, Nadire Duru, Gabriel Eades & Qun Zhou

  2. Department of Obstetrics, Gynecology & Reproductive Sciences at University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Peixin Yang

Authors
  1. Ramkishore Gernapudi
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  2. Yuan Yao
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  3. Yongshu Zhang
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  4. Benjamin Wolfson
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  5. Sanchita Roy
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  6. Nadire Duru
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  7. Gabriel Eades
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  8. Peixin Yang
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  9. Qun Zhou
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Corresponding author

Correspondence to Qun Zhou.

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Gernapudi, R., Yao, Y., Zhang, Y. et al. Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer. Breast Cancer Res Treat 150, 685–695 (2015). https://doi.org/10.1007/s10549-015-3326-2

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  • DOI: https://doi.org/10.1007/s10549-015-3326-2

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