Investigators from Princeton University’s Department of Molecular Biology say they have discovered a small RNA molecule that helps maintain the activity of stem tissue in both healthy and cancerous breast tissue. The study (“Normal plus cancerous mammary stem cells evade interferon-induced constraint with the miR-199a– LCOR axis”), which will be published in the 06 issue of Nature Cell Biology , shows that this microRNA promotes deadly forms of breast cancer and that suppressing the effects of this molecule could improve the efficacy of current breast cancer therapies.
Many tumors contain alleged “cancer stem cells” that can drive tumor formation. A few tumors, such as triple-negative breast cancers, are particularly fatal because they contain large numbers of cancer stem cells that self-renew and resist differentiation.
To identify factors that will help non-cancerous mammary gland stem cells (MaSCs) withstand differentiation and retain their capacity to self-renew, Yibin Kang, Ph. D. the Warner-Lambert/Parke-Davis Professor associated with Molecular Biology, and colleagues searched for microRNAs that can join and inhibit protein-coding messenger RNAs to reduce the levels associated with specific proteins. The researchers identified one microRNA, known as miR-199a, that helps MaSCs retain their stem-cell activity simply by suppressing the production of a protein called LCOR, which binds DNA to regulate gene expression. The team showed that whenever they boosted miR-199a levels in mouse MaSCs, these people suppressed LCOR and increased normal stem cell perform. Conversely, when they increased LCOR levels, they could curtail mammary gland stem cell activity.
Dr . Kang and colleagues found that miR-199a was also expressed within human and mouse breast cancer stem cells. Just as increasing miR-199a levels helped normal mammary gland stem cellular material retain their activity, the researchers showed that miR-199a enhanced the ability of cancer stem cells to form cancers. By increasing LCOR levels, in contrast, they could reduce the tumor-forming capacity of the cancer stem cells. In collaboration along with researchers led by Zhi-Ming Shao, Ph. D., the professor at Fudan University Shanghai Cancer Center within China, Dr . Kang’s team found that breast cancer individuals whose tumors expressed large amounts of miR-199a showed bad survival rates, whereas tumors with high levels of LCOR had a better prognosis.
Dr . Kang plus colleagues found that LCOR sensitizes cells to the associated with interferon-signaling molecules released from epithelial and immune tissues, particularly macrophages, in the mammary gland. During normal mammary gland development, these cells secrete interferon-alpha to promote cellular differentiation and inhibit cell division, the researchers found out. By suppressing LCOR, miR-199a protects MaSCs from interferon signaling, allowing MaSCs to remain undifferentiated and capable of self-renewal.
The microRNA plays a similar role throughout tumorigenesis, protecting breast cancer stem cells from the effects of interferons secreted by immune cells present in the tumor. “This is a very nice study linking a normal and malignant mammary gland stem cell program to protection from immune modulators, ” said Michael Clarke, M. D., the Karel H. and Avice N. Beekhuis Professor in Malignancy Biology at Stanford School of Medicine, Institute associated with Stem Cell Biology and Regenerative Medicine, who 1st discovered breast cancer stem cells but was not involved in this particular study. “It clearly has therapeutic implications for developing strategies to rationally target the breast cancer stem cells along with immune modulators. ”
Toni Celià -Terrassa, Ph. D., an associate research scholar in the Kang laboratory and the first author of the study, said, “This research unveils a new property of breast cancer stem cells that provide them advantages in their interactions with the immune system, and therefore this represents an excellent opportunity to exploit for improving immunotherapy associated with cancer. ”
“Interferons have been widely used for your treatment of multiple cancer types, ” added Dr . Kang. “These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by focusing on the miR-199a-LCOR pathway. ”