# Identification of Deregulated Proteins in Mutated BRCA1/2 Breast and Ovarian Cancers for Vectorized Biologics

## TL;DR

This study identifies proteins on cancer cell surfaces in BRCA1/2-mutated breast and ovarian cancers that could help deliver targeted therapies more safely and effectively.

## Contribution

The study identifies surface proteins specifically upregulated in BRCA1/2-mutated cancers, offering new targets for precision therapies.

## Key findings

- BRCA1/2-mutated cancers show distinct patterns of upregulated and downregulated surface proteins.
- Certain proteins like B3GNT7 and CTSV are linked to poor patient outcomes in BRCA2-mut breast cancers.
- Genes like CD6, CXCL9, and CXCL13 are associated with better outcomes and immune cell infiltration in BRCA1-mut ovarian cancers.

## Abstract

Breast and ovarian cancers with mutations in the BRCA1 and BRCA2 genes are especially sensitive to PARP inhibitors. These drugs block DNA repair mechanisms, causing cancer cell death. However, PARP inhibitors have demonstrated certain toxicity to healthy cells, limiting their safe use. To improve the precision and safety of these treatments, we sought to identify specific proteins on the surface of cancer cells that carry BRCA mutations. These proteins could serve as “flags” for targeted therapies, delivering treatment directly to cancer cells while sparing healthy tissues. We analyzed public datasets comparing gene activity in cancers with and without BRCA mutations. We identified several surface proteins that were more abundant in BRCA-mutated cancers. Some of these are linked to patient outcomes and the immune system, suggesting a potential role in cancer progression and immune response. By identifying these proteins, we can develop new therapies that use antibodies to deliver drugs, like PARP inhibitors, directly to cancer cells, reducing side effects and improving the effectiveness of current treatments for BRCA-mutated cancers.

Background: Administration of PARP inhibitors against breast and ovarian cancers with BRCA1 and BRCA2 mutations has shown clinical benefits in patients. However, these agents are also toxic and have a narrow therapeutic index. Objectives: In this work, we aimed to identify membrane proteins that are specifically upregulated in these cancers. Methods: We interrogated public datasets to analyze genes upregulated or downregulated when these mutations were present, compared with wild-type cancers. Surface protein expression and functional annotation analyses were also performed. Results: In breast cancer, we identified 11 upregulated and 44 downregulated transcripts in BRCA1-mut, while 10 upregulated and 57 downregulated transcripts were identified in BRCA2-mut cancers. In ovarian cancer, 79 transcripts were upregulated and 123 were downregulated in BRCA1-mut cancers, while five were upregulated and seven were downregulated in BRCA2-mut tumors. Regarding the biological function related to these genes, in BRCA1-mutated ovarian cancers, the main functions of upregulated genes included MHC assembly or regulation of the interferon gamma pathway; in BRCA2-mut ovarian cancers, regulation of phosphorylation and signaling; in BRCA1-mut breast cancers, cell damage repair and angiogenesis; and finally, in BRCA2-mut breast cancers, cytokine production and T-cell migration. Genes expressed in the surface membrane or extracellular matrix and related to patient outcomes included B3GNT7 and CTSV in BRCA2-mut breast cancers, exhibiting detrimental prognoses. CD6, CXCL9, and CXCL13 were associated with favorable outcomes in BRCA1-mutant ovarian cancers. The last three genes were also correlated with the infiltration of effector T cells and dendritic cells in ovarian tumors. Conclusions: In summary, we identified deregulated candidate genes that could be used as therapeutic targets.