Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/34763
Title: IDENTIFICATION OF NOVEL ONCOGENIC TARGET OF BREAST CANCER
Authors: ARPITA DATTA
Keywords: Breast cancer, SphK1, Chemotherapy, Oncogenic Target, Combination drug tratment
Issue Date: 26-Jul-2011
Source: ARPITA DATTA (2011-07-26). IDENTIFICATION OF NOVEL ONCOGENIC TARGET OF BREAST CANCER. ScholarBank@NUS Repository.
Abstract: Sphingosine kinases (SphKs) generate the production of sphingosine-1-phosphate (S1P), an oncogenic lipid mediator, from the phosphorylation of sphingosine, thereby regulating several processes important for cancer progression including cell growth and survival. We found that SphK1 levels are significantly increased in the majority of human breast tumors and breast cancer cell lines compared to matched normal tissues and cells. SphK1 expression was particularly pronounced in estrogen receptor (ER)-negative breast tumors, suggesting that SphK1 is a potentially important therapeutic target, as ER-negativity correlates with poorer prognosis. We have previously developed and validated the specificity of a novel SphK1-selective inhibitor developed by our group, compound 5c. We show that 5c is effective in counteracting the proliferation and survival of both ER-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells, but has minimal effects on MCF-10A breast epithelial cells. In MDA-MB-231 and MCF-7cells, 5c inhibits pro-survival signaling by reducing serum-induced ERK1/2 and Akt activation, as well as S1P export. Our studies indicate that whilst the early phase of ERK1/2 and Akt activation depends on intracellular S1P production by SphK1, the SphK1-dependent secretion of S1P acting on G protein-coupled receptors functions to sustain ERK1/2 and Akt signaling. 5c effectively attenuates both early and sustained ERK1/2 and Akt signaling by reducing SphK1-dependent production of intracellular and secreted S1P. Furthermore, combination treatment of 5c or siRNA against SphK1 with low doses of 5-fluorouracil (5-FU) and doxorubicin significantly potentiates their cytotoxic effects in ER-negative cancer cells. Moreover, 5c markedly reduced growth of ER-negative breast cancer xenograft tumors. As ER-negativity correlates with poor prognosis, a combination of SphK1 inhibitors with chemotherapeutic agents may lead to an effective treatment for breast cancer. Our data indicate that the inhibition of SphK1 counteracts key survival pathways and sensitizes breast cancer cells to chemotherapeutic drugs. The development of SphK1-targeted inhibitors may be explored in combination with current chemotherapeutic drugs for effective treatment of both ER-positive and ER-negative breast cancers.
URI: http://scholarbank.nus.edu.sg/handle/10635/34763
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