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mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression

Oncogene volume 33, pages 4548–4557 (2014)Cite this article

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Abstract

Although epidemiological and preclinical studies have shown the preventative effects of n-3 polyunsaturated fatty acids (PUFAs) on breast cancer, inconsistencies still remain in the data and the underlying mechanisms remain unclear. In this study, we identified mammalian target of rapamycin (mTOR) signaling, which plays an essential role in cell proliferation and breast tumorigenesis, as a target of n-3 PUFAs. In breast cancer cell lines, n-3 PUFAs rapidly and efficiently suppress both mTOR complex 1 (mTORC1) and mTORC2 and their downstream signaling, and subsequently inhibit cell proliferation and angiogenesis while promoting apoptosis. Further study indicates that stabilization of the mTOR-raptor complex by n-3 PUFAs may contribute to their inhibitory effect on mTORC1. Importantly, four complementary and well-controlled animal models were utilized to identify the role and molecular target of n-3 PUFAs in the prevention of breast carcinogenesis and progression, namely: (1) chemically induced mammary tumor rats with a high dietary intake of n-3 PUFAs; (2) nude mice implanted with mammary tumor cell lines stably expressing fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously; (3) fat-1 transgenic severe combined immune deficiency mice implanted with breast tumor cells; and (4) the fat-1 transgenic mouse mammary tumor virus-polyoma virus middle T oncogene double-hybrid mice, a model of aggressive breast cancer. In summary, dietary and endogenous n-3 PUFAs abrogate the activity of mTORC1/2 pathways in vitro and in vivo and prevent breast carcinogenesis, tumor growth and metastasis. Taken together, our findings convincingly clarify the causal relationship between n-3 PUFAs and breast cancer prevention and establish mTORC1/2 as a target of n-3 PUFAs.

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Acknowledgements

We greatly appreciate the gift of TSC2+/+ and TSC2−/− MEFs from Dr David J Kwiatkowski (Brigham and Women’s Hospital, Boston, MA, USA). This work was supported by the State Key Development Program for Basic Research of China (2009CB918904, 2013CB945203), National Natural Sciences Foundation of China (91029727), Guangdong Natural Science Foundation (s2012010008209) and Program for Changjiang Scholars and Innovative Research Team in University (IRT1142). TSC2+/+P53−/−and TSC2−/−P53−/− mouse embryonic fibroblasts (MEF) were provided by Dr David J Kwiatkowski (Brigham and Women's Hospital, Boston, MA, USA).

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Author notes

  1. Z Chen, Y Zhang, C Jia and Y Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Z Chen, Y Zhang, C Jia, P Lai, X Zhou, Q Song, Jun Lin & X Bai

  2. State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China

    Y Wang, Y Wang, Z Ren, Q Gao, Z Wan, A Zhao & Y Dai

  3. College of Life Sciences, Nankai University, Tianjin, China

    Z Zhao

  4. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    H Zheng

  5. Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou, China

    T Gao

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  1. Z Chen
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Correspondence to Y Dai or X Bai.

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Chen, Z., Zhang, Y., Jia, C. et al. mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression. Oncogene 33, 4548–4557 (2014). https://doi.org/10.1038/onc.2013.402

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