By silencing the gene normally associated with speech regulation and language development, a group of researchers at Beth Israel Deaconess Medical Center (BIDMC) enhanced breast cancer cell metastasis, suggesting a previously unknown connection between the FOXP2 transcription factor and breast cancer cell survival.
“We have identified a previously undescribed function for the transcription factor FOXP2 in breast cancer,” said Antoine Karnoub, PhD, senior investigator of the article published in Cell Stem Cell, “MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis,” in a news release from BIDMC. “We have found that depressed FOXP2 and elevated levels of its upstream inhibitor microRNA 199a are prominent features of clinically advanced breast cancers that associate with poor patient survival.”
At the heart of the study are mesenchymal stem cells (MSCs). MSCs produce a variety of factors that influence other cells’ behavior. Dr. Karnoub’s laboratory works with MSCs in the context of breast cancer development and metastasis and previously identified a role of MSCs in establishing 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,” summarized Dr. Karnoub.
In this most recent work, Dr. Karnoub’s laboratory identified an aberrant expression of microRNA-199a by MSCs that led to repressed expression of FOXP2 in breast cancer cells. This enabled cancer cell growth and migration.
“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,” continued Dr. Karnoub. “We then made a screen and serendipitously fished out a gene called FOXP2,” which had never been related to breast cancer previously.
“We were curious and wanted to find out the business of FOXP2 in breast cancer,” said Dr. Karnoub. “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.”
Implications of the work could provide new prognostic parameters that estimate breast cancer 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,” said Dr. 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.” Although it is difficult to suppress microRNA expression in the body, this may be another future avenue of research.
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