Wednesday, January 15, 2025
1/15/2025
Project Summary / Abstract This proposal addresses the challenge of closing the racial disparity gap in breast cancer mortality by identifying a contributing biological factor and developing therapeutic strategies to overcome its impact. The selenoprotein, SELENOF, was recently identified as a new tumor suppressor in breast cancer. The broad hypothesis is that lower SELENOF levels in African American patients contribute to the racial disparity in breast cancer mortality by driving tumor progression and poor patient outcome. Therefore, therapeutic strategies to mitigate its loss are needed to help close the disparity gap. The scientific premise for the hypothesis is based on the following: 1) the genomes of breast tumors from African Americans have a 5-10 fold higher frequency of SELENOF single nucleotide polymorphisms (SNPs), which account for lower SELENOF protein levels, 2) SELENOF mRNA expression is significantly lower in breast tumors from African American patients compared to Caucasians, and lower SELENOF levels predict shorter survival in these patients, 3) loss of SELENOF in normal breast epithelial cells resulted in increased proliferation and abrogated cell death, features of cellular transformation, and 4) overexpression of SELENOF in breast cancer cells induced cell death, blocked proliferation and survival, enhanced response to therapies, and inhibited tumor growth in vivo. The eukaryotic initiation factor 4a3 (eIF4a3) was identified as a translational repressor of SELENOF. The SELENOF locus SNPs are predicted to enhance eIF4a3’s binding affinity resulting in stronger repression of SELENOF translation. Preliminary data showed that pharmacologic inhibition of eIF4a3 results in increased SELENOF protein levels and reduced breast cancer cell viability in a SELENOF-dependent manner. Loss of SELENOF also resulted in hyperactivation of the kinase/RNase inositol-requiring enzyme 1 (IRE1), a master regulator of the unfolded protein response. This rendered cells highly susceptible to IRE1 inhibition, thus identifying a new vulnerability in these cells. Four aims are proposed: 1) Determine the mechanisms underlying SELENOF-induced cell fate in breast cancer, 2) Determine whether loss of SELENOF drives tumorigenesis by using African American derived xenografts and a murine model of breast cancer, 3) Determine the impact of SNPs on the regulation of SELENOF translation by eIF4a3, and 4) Determine whether eIF4a3 overexpression and the SNPs contribute to reduced SELENOF tumor levels and poor outcome in African American breast cancer patients. Our work will establish SELENOF as a new target to reduce racial disparity in breast cancer, and thus support the development of SELENOF-based therapies. In the clinic, SELENOF’s SNPs and levels can also serve as candidate biomarkers to identify African American patients at risk of aggressive disease. The distinct therapeutic strategies investigated here are likely to result in novel and more effective personalized medicine and may help close the disparity gap.
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