06 Nov Scientists Identify Factors That Promote Breast Cancer Metastases
MedicalResearch.com Interview with:
Antoine E. Karnoub, Ph.D.
Assistant Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School Center for Life Science 0634
Boston, MA 02215
Medical Research: What are the main findings of the study?
Dr. Karnoub: The main findings of the study are:
(1) that the metastatic propensities of cancer cells can be remarkably modulated by otherwise ‘normal’ mesenchymal stem/stromal cells found in their vicinity;
(2) that generation of highly malignant tumor-initiating cells can be significantly triggered by microenvironmental cues;
(3) that repression of the gene FOXP2 by a miR-199a-led microRNA network enables the propagation of cancer stem cell and metastatic traits in otherwise weakly metastatic cancer cells; and
(4) that such a signaling axis appears to forecast poor patient outcome.
Medical Research: What was most surprising about the results?
Dr. Karnoub: There are three surprising aspects of the findings.
- The first was the unexpected identification of a role for FOXP2, a gene that is otherwise linked to vocalization, speech, and language development, in human breast cancer pathogenesis.
- The second was the finding that such a gene was controlled not by one, but a series of interconnected molecules that conspire to inhibit its expression in the context of malignancy – perhaps an indication of multiple fail-safe mechanisms through which malignant cells can attenuate its expression.
- The third was that suppression of FOXP2 was sufficient, on its own, in propagating malignant traits in the cancer cells. These aspects altogether suggest that FOXP2 serves an important and perhaps determining role in malignant breast cancer.
Medical Research: What should clinicians and patients take away from your report?
Dr. Karnoub: There are two aspects of our work that have particular translational pertinence. First, we have identified a new set of players that regulate breast cancer malignancy. We have indicative evidence that the levels of such players, i.e., the levels of miR-199a, its miR network, and FOXP2, in human primary breast tumors correlate with overall patient survival, metastasis outcome, and relapse. Although these findings are consistent with the premise that such molecules are prognostic in breast cancer, more work is needed to affirm this notion in larger clinical cohorts. Then and only then will clinicians be able to use miR-199a and/or FOXP2 levels in tumor biopsies to risk-stratify patients upon diagnosis.
The second has to do with the therapeutic opportunities of diagnosed patients. It is possible that the sustenance of certain metastases depends upon the abilities of malignant cancer cells in these outgrowths to maintain expression of high levels of miR-199a, and/or low levels of FOXP2. If so, then therapeutics aimed at inhibiting miR-199a levels (therefore restoring FOXP2 normalcy) may prove efficacious in combating metastatic disease.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Karnoub: There are a number of questions that need to be answered, and we seem to be only at the beginning of this story. The translational aspects of the work, as we mention above, are useful and important aspects that can impact patient management down the line, and those represent natural avenues for future investigations that will assess the relevance of FOXP2 and its regulatory miR network as biomarkers and therapeutic targets in malignant breast (and perhaps other) cancers. From the pure scientific point of view, there are many questions that need to be investigated, but I think the most important revolves around determining what FOXP2 does in the normal setting, so that we understand how its inhibition promotes cancer progression.
Benjamin G. Cuiffo, Antoine Campagne, George W. Bell, Antonio Lembo, Francesca Orso, Evan C. Lien, Manoj K. Bhasin, Monica Raimo, Summer E. Hanson, Andriy Marusyk, Dorraya El-Ashry, Peiman Hematti, Kornelia Polyak, Fatima Mechta-Grigoriou, Odette Mariani, Stefano Volinia, Anne Vincent-Salomon, Daniela Taverna, Antoine E. Karnoub. MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis. Cell Stem Cell, 2014;