(T1230-04-22) The Paracrine Action of Mutant p53 in Breast Cancer

Purpose: Tumor suppressor p53 mutations have been identified in breast cancer-associated fibroblasts, correlating with a poor prognosis in patients. However, the effects of fibroblastic mutant p53 on breast cancer remain unclear. We aim to investigate whether and how p53R17H mutant in stromal fibroblasts impacts breast cancer. We hypothesize that fibroblastic p53R172H accelerates mouse mammary tumor development via paracrine signaling(s) that alter biological pathways in the tumor.

Methods: A cohort of MMTV-neu; Fsp-Cre; p53wm-R172H/+ (NP) female mice was established, which develops human-epidermal-growth-factor-receptor 2 positive mammary carcinomas and contains p53R172H, specifically in the fibroblasts. A cohort of MMTV-neu; Fsp-Cre (N) females was also established, where p53 remains intact in the stromal fibroblasts of HER2 tumors. Mice were monitored for tumor development. Tumors
were collected, and RNAs were extracted and sequenced, followed by differentially expressed gene
analysis and gene set enrichment analysis.

Results: The NP female mice exhibited a significantly shorter median tumor free survival than that of the N females. RNA-sequencing of NP and N tumors and mammary glands revealed large number of differentially expressed genes (DEGs) between tumor and mammary glands for each genotype. The DEGs that are solely present in the NP tumors verse N tumors were subjected to the Gene Sets Enrichment Analysis. Multiple signaling pathways, including the cholesterol homeostasis, apoptosis, PI3/AKT/mTOR and interferon alpha response, were found enriched in the NP tumors.

Conclusion: Our results show that fibroblastic mutant p53 promotes mammary tumor development, potentially through a paracrine mechanism that alters gene expression profiles in the tumor.