College of Nursing and Health Sciences, Flinders University of South Australia, Bedford Park, SA 5042, Australia.
Int J Mol Sci. 2018 Jan 31;19(2):420. doi: 10.3390/ijms19020420.
Sphingolipids, sphingolipid metabolizing enzymes, and their receptors network are being recognized as part of the signaling mechanisms, which govern breast cancer cell growth, migration, and survival during chemotherapy treatment. Approximately 70% of breast cancers are estrogen receptor (ER) positive and, thus, rely on estrogen signaling. Estrogen activates an intracellular network composed of many cytoplasmic and nuclear mediators. Some estrogen effects can be mediated by sphingolipids. Estrogen activates sphingosine kinase 1 (SphK1) and amplifies the intracellular concentration of sphingosine-1-phosphate (S1P) in breast cancer cells during stimulation of proliferation and survival. Specifically, Estrogen activates S1P receptors (S1PR) and induces growth factor receptor transactivation. SphK, S1P, and S1PR expression are causally associated with endocrine resistance and progression to advanced tumor stages in ER-positive breast cancers . Recently, the network of SphK/S1PR was shown to promote the development of ER-negative cancers and breast cancer stem cells, as well as stimulating angiogenesis. Novel findings confirm and broaden our knowledge about the cross-talk between sphingolipids and estrogen network in normal and malignant cells. Current S1PRs therapeutic inhibition was indicated as a promising chemotherapy approach in non-responsive and advanced malignancies. Considering that sphingolipid signaling has a prominent role in terminally differentiated cells, the impact should be considered when designing specific SphK/S1PR inhibitors. This study analyzes the dynamic of the transformation of sphingolipid axis during a transition from normal to pathological condition on the level of the whole organism. The sphingolipid-based mediation and facilitation of global effects of estrogen were critically accented as a bridging mechanism that should be explored in cancer prevention.
鞘脂类、鞘脂代谢酶及其受体网络被认为是信号转导机制的一部分，调控乳腺癌细胞在化疗过程中的生长、迁移和存活。大约 70%的乳腺癌是雌激素受体（ER）阳性的，因此依赖于雌激素信号。雌激素激活了一个由许多细胞质和核介质组成的细胞内网络。一些雌激素的作用可以通过鞘脂类来介导。雌激素激活了鞘氨醇激酶 1（SphK1），并在刺激增殖和存活时放大了乳腺癌细胞内鞘氨醇-1-磷酸（S1P）的浓度。具体来说，雌激素激活了 S1P 受体（S1PR）并诱导生长因子受体的反式激活。SphK、S1P 和 S1PR 的表达与 ER 阳性乳腺癌的内分泌抵抗和进展到晚期肿瘤阶段有关。最近，SphK/S1PR 网络被证明可以促进 ER 阴性癌症和乳腺癌干细胞的发展，并刺激血管生成。新的发现证实并拓宽了我们对正常和恶性细胞中鞘脂类和雌激素网络之间的交叉对话的认识。目前，S1PRs 的治疗性抑制被认为是一种有前途的化疗方法，适用于无反应性和晚期恶性肿瘤。鉴于鞘脂信号在终末分化细胞中具有重要作用，在设计特定的 SphK/S1PR 抑制剂时应考虑其影响。本研究分析了整个生物体水平上从正常到病理状态的转化过程中鞘脂轴的动态变化。基于鞘脂的调解和促进雌激素的全局效应被认为是一种桥梁机制，应该在癌症预防中进行探索。
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