Identification of actionable targets for breast cancer intervention using a diversity outbred mouse model

Jennifer B Jacob; Kuang-Chung Wei; Gerold Bepler; Joyce D Reyes; Andi Cani; Lisa Polin; Kathryn White; Seongho Kim; Nerissa Viola; Julie McGrath; Anthony Guastella; CongCong Yin; Qing-Shen Mi; Benjamin L Kidder; Kay-Uwe Wagner; Stuart Ratner; Victoria Phillips; Joanne Xiu; Prahlad Parajuli; Wei-Zen Wei

doi:10.1016/j.isci.2023.106320

Identification of actionable targets for breast cancer intervention using a diversity outbred mouse model

iScience. 2023 Mar 2;26(4):106320. doi: 10.1016/j.isci.2023.106320. eCollection 2023 Apr 21.

Authors

Jennifer B Jacob¹, Kuang-Chung Wei¹, Gerold Bepler¹, Joyce D Reyes¹, Andi Cani², Lisa Polin¹, Kathryn White¹, Seongho Kim¹, Nerissa Viola¹, Julie McGrath³, Anthony Guastella³, CongCong Yin⁴, Qing-Shen Mi⁴, Benjamin L Kidder¹, Kay-Uwe Wagner¹, Stuart Ratner¹, Victoria Phillips¹, Joanne Xiu³, Prahlad Parajuli¹, Wei-Zen Wei¹

Affiliations

¹ Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA.
² Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Clinical and Translational Research, Caris Life Sciences, Irving, TX75039, USA.
⁴ Department of Immunology, Henry Ford Health System, Detroit, MI48202, USA.

Abstract

HER2-targeted therapy has improved breast cancer survival, but treatment resistance and disease prevention remain major challenges. Genes that enable HER2/Neu oncogenesis are the next intervention targets. A bioinformatics discovery platform of HER2/Neu-expressing Diversity Outbred (DO) F1 Mice was established to identify cancer-enabling genes. Quantitative Trait Loci (QTL) associated with onset ages and growth rates of spontaneous mammary tumors were sought. Twenty-six genes in 3 QTL contain sequence variations unique to the genetic backgrounds that are linked to aggressive tumors and 21 genes are associated with human breast cancer survival. Concurrent identification of TSC22D3, a transcription factor, and its target gene LILRB4, a myeloid cell checkpoint receptor, suggests an immune axis for regulation, or intervention, of disease. We also investigated TIEG1 gene that impedes tumor immunity but suppresses tumor growth. Although not an actionable target, TIEG1 study revealed genetic regulation of tumor progression, forming the basis of the genetics-based discovery platform.

Keywords: Cancer; Genomics; Molecular biology; Transcriptomics.