Scientists at Rockefeller University say they have discovered a major clue to the role short stretches of genetic fragments floating inside cells play in the body. The also believes it might have opened up a new frontier in the fight against breast cancer.

Specifically, Sohail Tavazoie, M.D., Ph.D., and his colleagues have found that these particular molecules, known as transfer RNA (tRNA), appear to be capable of reducing the growth and spread of breast cancer cells.

“This is a new basic mechanism the body uses to control the growth of cancer,” says Dr. Tavazoie, Leon Hess Associate Professor and head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology. “We plan to explore it further, so hopefully it will open up new ways of curbing cancer that we have never tried before and reveal new basic insights on how genes are regulated inside our cells.”

The group’s study (“Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement”) appears in Cell.

Scientists have found tRNA fragments in all walks of life, and they consistently increase in number when cells are exposed to low oxygen levels and other forms of cellular stress. But their purpose in the body has remained mysterious.

The research, led by postdoctoral fellow Hani Goodarzi, Ph.D., discovered that breast cancer cells generate tRNA fragments when exposed to low levels of oxygen. And cancer cells that carry more of these particular genetic fragments are less likely to metastasize. What's more, adding these fragments to cells reduced the growth and progression of cancer; blocking the fragments, in turn, led to the opposite effect.

Looking closer, the researchers saw that tRNA fragments that come from specific tRNAs (glutamic acid, aspartic acid, glycine, tyrosine) bind to an oncogene, which normally binds to other RNAs and increases their numbers, causing them to make more of the oncogenes that help cancer cells divide and spread. “These tRNA fragments bind the oncogene called YBX1 and push out the other RNAs that encode for oncogenes, reducing cancer cells' ability to grow and metastasize. By doing so, they represent a new class of molecules in the cell we call tumor suppressors,” says Dr. Goodarzi.

These tRNA fragments are demonstrating an entirely novel way of regulating gene expression, Dr. Tavazoie says. By blocking YBX1's ability to bind other RNAs whose expression YBX1 increases, tRNA fragments are playing a part in how the body expresses genes.

“Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action,” wrote the investigators. “This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.”

It makes sense that the number of tRNA fragments would increase in periods of cellular stress, such as when the cell is exposed to low oxygen levels, continues Dr. Tavazoie. “Cells can sense whether they don't have sufficient energetic currency that occurs during low oxygen states, and tRNA fragments help suppress cells' growth rate so they can preserve their energy and nutrients for when the stress resolves.”

Of course, aggressive breast cancer cells often find ways to sidestep the body's efforts to control them, including those involving these tRNA fragments. “We're very interested in figuring out how aggressive breast cancer cells stop the production of tRNA fragments,” explains Dr. Tavazoie. “It's exciting that these cancer cells are revealing a completely new way by which expression of oncogenes is regulated as a means of controlling cancer growth.”