Stromal Fibroblast Mutant Trp53 Promotes Mammary Tumor Development via Enhanced Secretion of Paracrine Factors

Mutations in the tumor suppressor gene TP53 have been identified in breast cancer-associated fibroblasts and are associated with poor patient prognosis. However, the functional impact of fibroblastic mutant p53 on breast cancer development remains unclear. To investigate this, we compared female mice harboring HER2-driven mammary tumors with a fibroblast-specific Trp53 mutation (NP) to those with wild-type fibroblastic Trp53 (N). NP mice exhibited significantly shorter median tumor-free survival than N mice. RNA sequencing of NP and N tumors and mammary glands revealed numerous differentially expressed genes (DEGs) between tumors and the corresponding glands in both genotypes. Notably, the NP tumors showed enrichment of several signaling pathways, including PI3K/AKT/mTOR. Additionally, twenty DEGs encoding secreted proteins were identified between NP and N mammary glands. Among these, Saa1 and Saa2 were also upregulated in human breast tumors with mutant TP53 compared to those with wild type TP53. Previous studies have implicated SAA1, SAA2, and THBS4 in promoting tumor progression via the PI3K/AKT pathway. Consistently, supplementing primary HER2 tumor cultures with recombinant SAA1, SAA2, or THBS4 peptides enhanced tumor cell proliferation and migration. Together, these findings uncover a mechanism by which fibroblastic mutant p53 promotes mammary tumorigenesis—through upregulating secretory proteins such as SAA1, SAA2, and THBS4 in the stroma, thereby enhancing PI3K/AKT signaling and tumor progression.