Abstract
Breast cancer is a leading cause of morbidity and mortality among women. Metastasis is initiated after epithelial-mesenchymal-transition (EMT). We have found a connection between EMT markers and the expression of four microRNAs (miRs) mediated by the signaling enzyme phospholipase D (PLD). Low aggressive MCF-7 breast cancer cells have low endogenous PLD enzymatic activity and cell invasion, concomitant with high expression of miR-203, -887, and -3619 (that decrease PLD2 translation and a luciferase reporter) and miR-182 (targeting PLD1) that are, therefore, "tumor-suppressor-like" miRs. The combination miR-887+miR-3619 abolished >90% of PLD enzymatic activity. Conversely, post-EMT MDA-MB-231 cells have low miR expression, high levels of PLD1/2, and high aggressiveness. The latter was reversed by ectopically transfecting the miRs, which was negated by silencing miRs with specific siRNAs. We determined that the molecular mechanism is that E-cadherin triggers expression of the miRs in pre-EMT cells, whereas vimentin dampens expression of the miRs in post-EMT invasive cells. This novel work identifies for the first time a set of miRs that are activated by a major pre-EMT marker and deactivated by a post-EMT marker, boosting the transition from low invasion to high invasion, as mediated by the key phospholipid metabolism enzyme PLD.
Highlights
Breast cancer is a leading cause of morbidity and mortality among women
We have found a connection between EMT markers and the expression of four microRNAs mediated by the signaling enzyme phospholipase D (PLD)
Phospholipase D (PLD) Is Associated with Increased Invasiveness in Breast Cancer Cells—Due to its positive effect on cancer cell migration, we looked at the levels of PLD gene expression in three breast cell lines after increasing time of incubation with epidermal growth factor (EGF)
Summary
Breast cancer is a leading cause of morbidity and mortality among women. It is estimated that 1 in 8 women in America will develop invasive breast cancer in their lifetime [1]. The active miR is able to associate with the 3Ј-UTR of target mRNA molecules with partial complementarity [15] It is estimated more than half of the protein coding genes can be regulated by miRs, allowing miR regulation to affect most cellular processes [16]. Expression profiles of various miR molecules have been shown to vary greatly in cancer when compared with healthy tissue [17,18,19]. It would seem inherent that miRs could play a major role in various aspects of cancer, and recent studies have found that expression profiles of several miR molecules varied greatly in cancer when compared with healthy tissue [17, 18]. It is unlikely that only one miR will be enough to act on regulating mammalian isoforms PLD1 and PLD2, as it appears to be the norm that several miRs will cooperate to impede translation of a particular protein
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
