A recent study has demonstrated that the silencing of the transcription factor FOXP2 endows breast cancer cells with malignant traits that permit them to survive and thrive. The research team at Beth Israel Deaconess Medical Center (MA, USA) published their data on this link recently online in Cell Stem Cell.
“We have identified a previously undescribed function for the transcription factor FOXP2 in breast cancer,” explained senior author Antoine Karnoub (Beth Israel Deaconess Medical Center). “We have found that depressed FOXP2 [a member of the forkhead family of transcriptional regulators] and elevated levels of its upstream inhibitor microRNA-199a are prominent features of clinically advanced breast cancers that associate with poor patient survival.”
Karnoub’s lab investigates the role of mesenchymal stem cells (MSCs) in the development and metastasis of breast cancer. Previous research by the group demonstrated that MSCs respond to breast tumors akin to the way they react to a wound or infection and that they also participate in the formation of the breast tumor stroma.
“We think that by direct actions on the cancer cells and by manipulating other cells in the microenvironment, MSCs end up providing cancer cells with better abilities to survive and a safe haven in which to thrive,” explained Karnoub.
Despite growing knowledge of the role of MSCs in breast malignancy, the underlying molecular responses of breast cancer cells to MSC influences have not been fully defined. The investigators therefore set out to specifically identify the role that microRNAs were playing in the process.
“After we found that miRNA-199a instigated in the cancer cells by MSCs was indeed promoting these cancer stem cells phenotypes and was facilitating cancer metastasis, we probed the mechanistic details of miR-199a’s actions,” explains Karnoub. “miRNAs function predominantly by suppressing target mRNA expression, and we analyzed an overwhelming majority of the published targets that have been associated with these miRNAs, but none was repressed in our systems. We then made a screen and serendipitously fished out a gene called FOXP2.”
“We were curious and wanted to find out the business of FOXP2 in breast cancer,” he adds. “Surprisingly, we found that its suppression in the tumor cells was sufficient to expand cancer stem cell traits and caused the cancer cells to metastasize much more vigorously.”
The findings support previous results that highlighted microRNA-199a upregulation and FOXP2 repression as clear features of aggressive clinical breast cancers, in addition to representing independent prognostic parameters for overall patient survival.
“We are one step closer to understanding how cells in the tumor microenvironment, such as MSCs, promote the malignancy of neighboring cancer cells,” explained Karnoub. “We’re now more closely investigating FOXP2’s potential role as a metastasis suppressor that needs to be downregulated for metastasis to take place.”