Abstract Background: Germline BRCA2 mutations substantially increase breast cancer risk, but penetrance varies, indicating a role for genetic modifiers. These modifiers can influence tumor initiation and progression even among individuals with the same BRCA2 variant, and their discovery and characterization can improve risk prediction and therapeutic stratification. For many GWAS-identified BRCA2 modifiers, the biological mechanisms are still unclear. We examined STARD13, a cytoskeletal regulator and putative tumor suppressor identified in prior BRCA2 GWAS signals, may intersect functionally with the Hippo pathway through effects on RhoA-actin dynamics that influence LATS2 activity, which in turn regulates YAP/TAZ-mediated proliferation and genomic stability. Because LATS2 supports genomic integrity and suppresses oncogenic signaling, we hypothesized that disruption of the STARD13 and LATS2 axis may modify BRCA2-associated phenotypes in breast epithelial cells. Methods: BRCA2 mutants were generated in breast epithelial cell lines using CRISPR/Cas9 genome editing. Allele-specific regulatory effects of the SNPs were assessed by luciferase reporter assays. To investigate STARD13 as a genetic modifier, siRNA- and shRNA-mediated knockdown was performed in wild-type and BRCA2 mutant cells. LATS2 expression was quantified by qRT-PCR. Functional assays measuring proliferation, apoptosis, and DNA damage sensitivity evaluated the impact of STARD13 knockdown in different BRCA2 contexts. Results: In wild-type BRCA2 cells, STARD13 knockdown upregulated LATS2 expression, indicating activation of a compensatory tumor suppressor pathway. In contrast, In BRCA2-mutant cells, loss of STARD13 fails to induce the compensatory increase in LATS2 seen in BRCA2-wild-type cells, identifying STARD13 as a modifier of the BRCA2-deficient state. These data implicate LATS2 as a modifier of BRCA2 via STARD13-dependent mechanisms. Ongoing experiments in BRCA2 mutant cell lines and organoids are examining effects on DNA damage, repair, colony formation, gene expression, and responses to PARP inhibitors using shRNA and CRISPR knockouts. Conclusions: Our findings support STARD13 as a potential genetic modifier of BRCA2, influencing the activity of LATS2 tumor suppressor and linking cytoskeletal signaling with DNA repair pathways. The differential regulation of LATS2 in wild-type versus BRCA2 mutant backgrounds suggests a novel axis that may underlie variation in BRCA2 penetrance and cancer risk. These studies aim to elucidate the STARD13-LATS2-BRCA2 interaction network as a determinant of BRCA2 penetrance, as a potential biomarker to allow targeting to decrease penetrance of hereditary breast cancer in affected kindreds. (Supported by Breast Cancer Research Foundation and Niehaus Center for Inherited Cancer Genomics). Citation Format: SHIV PRAKASH VERMA, Mitul Waghmare, Sanchari Bhattacharyya, Catherine Fanjoy, Shao Hong, Xu Zhang, Jonathan Amsalem, Yelena Kemel, Minna Lee, Matthew Buas, Zsofia Stadler, Pedram Razavi, Mark Robson, Sarat Chandarlapaty, Kenneth Offit, Vijai Joseph. STARD13-LATS2 Axis as a potential genetic modifier of BRCA2 in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6817.
Verma et al. (Fri,) studied this question.