Getting to the Bottom of Racial Disparities in Breast Cancer
Cancer incidence and mortality are declining in the U.S. overall, yet certain groups continue to have an increased risk compared to others. Women of European heritage have a slightly higher likelihood of developing breast cancer, for instance, but women of African heritage remain more likely to die from their disease at any age. Triple-negative tumors, known as the most aggressive subtype, also occur twice as often in women of African heritage compared to their European counterparts.
The biological reasons for these racial disparities in breast cancer still aren’t fully understood, but a new study highlights a prognostic biomarker called Kaiso that may provide some insight. Kevin Gardner, MD, PhD, professor of pathology and cell biology at Columbia's Vagelos College of Physicians & Surgeons, and his colleagues found that the predictive value of Kaiso varies across racial groups and differs based on its location within tumor cells. The results were published in Communications Biology.
“Though the major focus of health disparities research is driven by the social and behavioral sciences, the elucidation of the role played by biology and how that role may be differentially influenced by genetic ancestry will be essential for improving the diagnosis, treatment, and prevention of breast cancer health disparities," says Dr. Gardner, a member of the Herbert Irving Comprehensive Cancer Center (HICCC).
Initially, many researchers attributed the racial disparities seen in breast cancer to differences in socioeconomic status. But more recent studies — including those focused on Kaiso — have revealed that genetic risk factors and predisposition play an important role.
Kaiso, named after a genre of Caribbean music that has its origins in West Africa, is a transcription factor that regulates the expression of genes. Multiple studies have shown that accumulation of the protein in the nucleus of cells can drive transcriptional programs that increase breast cancer growth and metastasis. It has previously been correlated with aggressive subtypes like triple-negative breast cancer and shorter metastasis-free survival in women of African heritage.
“Women of African ancestry in the United States have a 40% higher mortality from breast cancer than women of European ancestry,” says Dr. Gardner, who recently co-edited a book titled The Sciences of Health Disparities Research that integrates the various disciplines of the field — including genetics, public health, health care policy, and epidemiology — into a single, comprehensive volume. “A central goal of the work in our group is to define and understand the key biological drivers for this disparity and how they interact and are shaped by other socioeconomic determinants of health.”
Dr. Gardner and his colleagues leveraged machine learning to analyze the subcellular distribution of Kaiso for 555 tumors from a racially diverse cohort of patients based in eastern North Carolina. While the bulk of prior research has focused on levels of the biomarker inside the nucleus, where its presumed role was in gene regulation, the investigators also found a strong association between disease outcome and the location of Kaiso in cellular compartments profile outside of the nucleus, in the cytoplasm.
The results demonstrated higher levels of cytoplasmic Kaiso — but not nuclear Kaiso — in the subtypes of cancer known to be more aggressive, including triple-negative breast cancer and breast cancers that overexpress human epidermal growth factor receptor 2 (HER2+). Both types of Kaiso were highly correlated with poor breast cancer survival, although cytoplasmic Kaiso was significantly more predictive.
In addition, like its nuclear form, cytoplasmic Kaiso was more predictive of overall survival in women of African heritage with triple-negative disease showing the poorest survival rates. The team also detected race-specific differences in the tumor microenvironment, with a trend towards greater suppression of immune cells in the tumors of women of African heritage, an observation that was recently confirmed by investigators in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium.
Overall, the study highlights the importance of measuring both nuclear and cytoplasmic Kaiso as prognostic biomarkers of breast cancer. Such an approach has the potential to guide future treatment strategies, including whether to use certain immune checkpoint inhibitors, a therapeutic decision that may have particular relevance in patients of African heritage. Dr. Gardner adds that the racially disparate results emphasize the need for a greater diversity of racial and ethnic groups in clinical trials.
“The underlying causes for overserved racial differences in survival and response to therapy are likely to be highly complex, involving multiple features where biology, behavior, and the environment interact in many ways that remain to be defined,” he says. “Fully understanding these linkages will require more studies that include more members from under-represented minority populations in interdisciplinary studies that span the scope of scientific inquiry from the bench, to the bedside, and to the community."