A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer

Abstract

Background In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYβB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYβB2 pseudogene, CRYβB2P1, and not CRYβB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYβB2 and CRYβB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYβB2 and CRYβB2P1 to racial disparities. Methods Custom scripts for CRYβB2 or CRYβB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. Results We provide evidence that CRYβB2P1 is expressed at higher levels in breast tumors compared to CRYβB2, but only CRYβB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYβB2, CRYβB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYβB2P1 may function as a non-coding RNA to regulate CRYβB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYβB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYβB2 and CRYβB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. Conclusions Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYβB2 and CRYβB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules.

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

“…In addition to CYP4Z2P, some pseudogene-derived lncRNAs were also found to function as oncogenes in breast cancer. For example, Liu et al (2017a) confirmed that SUMO1P3 promoted proliferation, migration and invasion of breast cancer; Barrow et al (2019) found that CRYbetaB2P1 was upregulated in breast cancer and facilitated progression of breast cancer by increasing CRYbetaB2 expression; demonstrated that FTH1P3 led to paclitaxel resistance of breast cancer. PTTG3P was markedly upregulated in breast cancer samples compared with normal controls and its upregulated linked to poor prognosis of patients with breast cancer .…”

Differential expression of COVID-19-related genes in European Americans and African Americans

“…Genetics of human populations contribute to the propensity and severity of diseases 37,39,41,41,45,[60][61][62][63][64][65] . Sometimes the contribution is straightforward; a single allele variation found in Ashkenazi Jews, causes the vast majority of Tay-Sachs disease 66 .…”

“…For example, obtaining adequate sample sizes for statistical analysis of populations is very important but difficult or expensive to address. Ethnic bias and practical factors (such as subject availability) often result in insufficient numbers of subjects from many populations to be represented in medical studies; this lack of representation prevents the development of precise prognosis or therapy based on genetics 39,97 . Similarly, diverse socioeconomic contexts may not be well represented among the individuals sampled.…”

“…Ethnic bias and more practical factors (such as subject availability) often cause insufficient numbers of subjects from many populations to be represented in studies; this lack of representation prevents the development of precise prognosis or therapy based on genetics 39,100 .…”

“…COVID-19 cases and deaths are disproportionately higher among African Americans; this is often attributed to a complex combination of socio-economic factors 15,36,37 . However, a number of studies have shown differences in genes expression among races [38][39][40][41] . Gene expression reflects the interaction between environmental/physiological and genetic influences.…”