Omics analyses of a somaticTrp53R245W/+breast cancer model identify cooperating driver events activating PI3K/AKT/mTOR signaling

• DOI: 10.1073/pnas.2210618119
• Publication Date: 2022-11-02T18:50:06Z
• Authors: Xiaojie Yu; Yun Zhang; Shunbin Xiong; Joy M. McDaniel; Chang Sun; Gilda P. Chau; Jovanka Gencel-Au...; Dhruv Chachad; Rhiannon L. Morri...; Xiayu Rao; Jing Wang; Guillermina Lozano
• Keywords: TOR Serine-Threonine Kinases; Breast Neoplasms; Biological Sciences; 3. Good health; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; 0302 clinical medicine; Animals; Humans; Female; Tumor Suppressor Protein p53; Proto-Oncogene Proteins c-akt; Signal Transduction

Alterations of the tumor suppressor TP53 , one most common events in cancer, alone are insufficient for development but serve as drivers transformation. We sought to identify cooperating through genomic analyses a somatic Trp53 R245W mouse model (equivalent R248W hot spot mutation human cancers) that recapitulates metastatic breast–cancer development. identified lesions similar those found breast cancers. Moreover, we activation Pi3k/Akt/mTOR pathway tumors via mutations Pten Erbb2 Kras and/or recurrent Pip5k1c stabilizes protein and activates signaling. Another PIP5K1C family member, PIP5K1A is coamplified with PI4KB 18% cancer patients; both encode kinases responsible production PI3K substrate, phosphatidylinositol 4,5-bisphosphate. Thus, PI3K/AKT/mTOR signaling major cooperative driving breast-cancer Additionally, combination two US Food Drug Administration (FDA)-approved drugs, tigecycline metformin, which target oxidative phosphorylation downstream signaling, inhibited cell growth may be repurposed treatment. These findings advance our understanding how mutant p53 drives breast-tumor pinpoint importance expanding therapies