Study Reveals Stark Racial Differences in Triple Negative Breast Cancer Transcriptomes
The findings could explain why African American women are more prone to invasive, treatment-resistant breast tumors.
Triple negative breast cancer, named for the absence of receptors for estrogen, progesterone, and the human epidermal growth factor, is the one of the most aggressive forms of the disease with limited options for treatment. This breast cancer subtype is more common in Black or African American women, who are also prone to exceptionally aggressive and faster-spreading form of the disease. Now, Thomas Jefferson University researchers offer new insight into these racial disparities by demonstrating drastic differences between White and Black or African American patients’ tumor transcriptomes.
The results, published in Cancer Research, demonstrate that these two groups of triple negative patients not only produce different abundances of messenger RNAs (mRNAs)—a molecule that translates the DNA blueprint into the protein building-blocks of the cell—but also vary greatly in the types of molecules their tumor cells use to regulate mRNA expression. These differences affect multiple molecular pathways known to be important for cancer.
“The scientific community has been aware of racial disparities in this cancer subtype. However, the molecular underpinnings of these disparities had eluded us,” says Isidore Rigoutsos, Richard W. Hevner Professor of Computational Medicine, Director of the Computational Medicine Center, and member of the Sidney Kimmel Cancer Center at Thomas Jefferson University. “Our study suggests that mRNA abundances are controlled differently, by different RNA regulatory molecules, in White versus Black or African American patients. This can potentially change the way people think about the molecular biology of this cancer and lead to improved treatments that account for racial differences.”
Dr. Rigoutsos and his team previously demonstrated that the abundance of microRNA (miRNA) isoforms and transfer RNAs (tRNAs) fragments—two categories of regulatory RNAs that can alter the number of messenger RNA, and therefore the abundance of proteins produced—differs based on gender, race, population origin, tissue, and disease. Since miRNA isoforms and tRNA fragments control the abundance of mRNAs and the proteins these mRNAs produce, these findings prompted the Rigoutsos team to investigate whether differences in these two regulators could explain racial disparities in the incidence and progression of triple negative breast cancer.
When PhD candidate Aristeidis Telonis and Dr. Rigoutsos analyzed data from White and Black or African American patients’ normal and cancerous breast samples from The Cancer Genome Atlas data repository, they revealed that miRNA isoforms and tRNA fragments act very differently in the two races; in White patients, the abundance of mRNAs are mainly regulated by tRNA fragments while in Black patients, they’re almost exclusively controlled by miRNA isoforms—indeed, the control of mRNAs by tRNA fragments is non-existent in these patients.
“We found that the same mRNAs and the same molecular pathways are disrupted in both races,” says Dr. Rigoutsos. “But surprisingly, the abundance of these mRNAs seems to be controlled in different ways and by different regulators in the White and Black or African American triple negative patients. This was very unexpected.”
While the researchers don’t yet know whether increased disease severity in Black or African American patients results from the diminished regulatory control of mRNAs by tRNA fragments or increased control by miRNA isoforms, the team is working on sorting this out.
“Our study also reveals that there are racial differences in how the miRNA isoforms and tRNA fragments interact with mRNAs in normal breast tissue,” says Dr. Rigoutsos. “Are these differences responsible for what eventually manifests as a racial disparity in triple negative breast cancer?”
“This fast-emerging complexity is an opportunity to develop improved personalized diagnosis and treatment,” says Dr. Rigoutsos. “The transcriptomic heterogeneity uncovered in the present study and earlier studies by my team could one day guide better-targeted diagnostic and treatment options.”
The study was funded by a William M. Keck Foundation grant, an NIH grant (R21-CA195204) and Thomas Jefferson University funds. The funders had no role in the study design, conduct of the experiments, and interpretation of the data.
Article reference: A.G. Telonis & I. Rigoutsos, “Race disparities in the contribution of miRNA isoforms and tRNA-derived fragments to triple-negative breast cancer,” Cancer Research, doi:10.1158/0008-5472.CAN-17-1947, 2017.
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