The Fragile X Protein binds m RNA s involved in cancer progression and modulates metastasis formation

Abstract

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression.

A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response

“…The absence of FMRP promotes apoptosis (Jeon et al, 2011) and telomere erosion in the fragile X patients, which is a major hallmark of genomic instability (Jenkins et al, 2008). In addition, fragile X patients have been reported to display a lower incidence of cancer (Schultz-Pedersen et al, 2001), whereas an increase in FMRP levels promotes tumor metastasis (Luca et al, 2013). Lastly, given that the loss of FMRP function leads to a common form of intellectual disability and autism, it is tempting to speculate that the role of FMRP in the DDR might represent a novel, previously unappreciated contributing factor to the development of the fragile X syndrome.…”

Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome

“…It has been reported that higher amounts of FMR1 mRNA and FMRP correlate with a more aggressive form of breast cancer (59). This correlation was attributed to FMRP binding to E-cadherin and vimentin mRNAs and regulating epithelial-to-mesenchymal transition, a hallmark of cancer invasion and metastasis , (57, 59–62).…”

“…This correlation was attributed to FMRP binding to E-cadherin and vimentin mRNAs and regulating epithelial-to-mesenchymal transition, a hallmark of cancer invasion and metastasis , (57, 59–62). Conversely, loss of BMP signaling in mammary carcinomas can accelerate metastasis, indicating that BMP plays a tumor suppressor role (63).…”

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

“…For instance, FMR1, a FRAXA-residing gene which harbors trinucleotide repeat expansions in Fragile X syndrome (FXS) patients, correlates with aggressiveness and lung metastasis probability in triple-negative breast cancer. Overexpression of the FMR1 protein enhances, whereas its downregulation inhibits breast cancer metastasis [51]. Links between FMR1 and other cancer types have been recently reported [52].…”