Abstract
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 in vivo. 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.
Highlights
Steroid hormone Estrogen is the key physiological factor for normal development and differentiation of mammary and other reproductive tissues [1,2,3]
The role of Sphingosine kinase (SphK) as mediator of estrogen-induced growth-promoting effects was discovered in MCF-7 human breast cancer cells more than a decade ago [5,6]
It is important to note that the estrogen-initiated sphingosine kinase 1 (SphK1)-mediated Epidermal growth factor receptors (EGFR) transactivation involved matrix metalloproteases (MMP) and c-Src, as the signaling was inhibited in the presence of Src-specific inhibitor PP2 and MMP inhibitors o-phenanthroline or GM6001 [14]
Summary
Steroid hormone Estrogen is the key physiological factor for normal development and differentiation of mammary and other reproductive tissues [1,2,3]. Epidermal growth factor receptors (EGFR) influence the estrogen pathway and regulate breast cancer cell survival and spreading [13], and influence the SphK1 network [14,15,16]. This review will account for discovered milestones of the SphK/S1P/S1PR signaling axis including the sphingolipids role in maintenance of homeostasis and estrogen-linked responses in normal and malignant cells. It will discuss the potential directions of future experimental work that should uncover clinically valuable details of sphingolipid signaling crosstalk with major regulatory agents such as hormones, cytokines, and growth factors. SsipghnKa/lSin1gP wsiagsnaimlinpglicwaatesdiminptolictahteedmianitnotetnhaenmceaionftebnaasnicceceollf fbuanscictiocenlsl finucnlcutdioinsg icnecllugdroinwgthc,edllivgirsoiownt,hm, doibviilsitiyo,na,nmdosbigilnitayl,traanndsdsuigcntiaolnt.rSaonmsdeuoctfiothne.sSeobmaseicoffutnhcetsioenbsaasriec faulsnoctcioonntsroallreed ablysostecroonidtrohlolermd obnye esstterroogiedn,heosrpmecoinalelyeisntrEoRg-eenx,preesspseincigalblyreaisnt mERam-emxparreysscianngcebrrceeallsst. mammary cancer cells
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