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Targeting the S1P Axis and Development of a Novel Therapy for Obesity-Related Triple-Negative Breast Cancer

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Technical Report,01 Sep 2015,31 Aug 2016

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Virginia Commonwealth University Richmond United States

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The majority of breast tumors express the estrogen receptor ER, which plays important roles in breast cancer pathogenesis and progression, and hormonal therapies, such as tamoxifen, are the first line of adjuvant therapy 1, 2. Unfortunately, half of these patients will ultimately fail therapy due to de novo or acquired resistance. Moreover, patients with ER, progesterone receptor PR and human epidermal growth factor receptor 2 HER2, also known as ErbB-2 triple negative breast cancer TNBC, which is aggressive with high recurrence, metastatic, and mortality rates 3, do not respond to hormonal therapies and have limited treatment options. Epidemiological and clinical studies indicate that obesity, which is now endemic, increases breast cancer risk and is associated with worse prognosis 4, which may be due in part to the high frequency of TNBC and ineffectual hormonal therapy 5. However, the links between obesity and breast cancer are not understood and is the focus of our study. As hormonal therapy is so effective with relatively few side effects, the possibility of reversing hormonal unresponsiveness is an appealing treatment approach. Our study will lead to novel therapies that will overcome the overarching challenges of developing safe and effective drugs for treating obesity-promoted cancers and TNBC and will identify the bioactive sphingolipid metabolite, sphingosine-1-phosphate S1P, produced by sphingosine kinases SphK1 and SphK2, as a critical factor that links obesity and chronic inflammation to drive breast cancer growth and metastasis.

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