Abstract PS4-04-12: Adaptive selection of p53 mutation metaplastic phenotypes in estrogen-independent progression of ER+ tumors: A mechanism for acquired resistance to hormonal therapy

Abstract Introduction: Estrogen receptor positive (ER+) subtypes of mammary adenocarcinoma comprise 79% of all breast cancer diagnosis and 67% of all breast cancer mortality. The paucity of models of ER+ mammary cancer that mimic human disease and response to treatment has limited critical preclinical study of mechanisms and new therapies for ER+ breast cancer. The Stat1 knockout, 129S6/SvEvTac-Stat1tm1Rds (Stat1-/-), females develop luminal type FoxA1+, ER+, and PR+ mammary carcinomas after prolonged latencies. Initial studies showed that a cell line derived from a Stat1-/- mammary carcinoma was tumorigenic in syngeneic mice, but non-tumorigenic in ovariectomized (Ovx) mice. Methods: Syngeneic tumor transplants, either from the SSM2 cell line established as a primary culture from a single mammary tumor in a Stat1-/- female, or from direct biopsy transplants of two different mammary tumors in Stat1-/- female mice, were allowed to establish growth under intact ovary syngeneic (129SvEv) female mice. After 3 weeks, these tumor bearing mice were Ovx'ed and growth was monitored, and tumor tissues harvested for analysis. Results: Ovx performed after SSM2 tumors establish growth results in ovarian hormone independent growth. The viable post-Ovx tumors were primarily composed of metaplastic CK14+ basal type cells with a high percentage p53 immunohistochemistry (IHC) positive “mutation pattern”, rather than the original luminal type tumors with low percent “wild type” pattern p53. Comparing whole exome sequences of ER+ Stat1-/- mammary tumors before and after Ovx, revealed basal keratins, mesenchymal (EMT) phenotypes, and unique mutation profiles in genes, including Trp53 and Prlr, in the estrogen-independent tumors (Prlr mutations were seen in both estrogen dependant and independant tumors). Our experimental findings are consistent with the clinical evidence of tumor heterogeneity of ER+ breast cancers in patients in recent whole genome sequencing studies. Similarly, spontaneous Stat1-/- tumors with high percentage p53 “mutation pattern” were more basaloid and grew rapidly after Ovx, while retaining high expression of ER and FoxA1. Conclusions: This study demonstrates that the STAT1-/-, ER+ estrogen dependent breast cancers can become resistant to through clonal selection of mammary cells comprised of metaplastic p53+/CK14+ basaloid cells. This implies that p53 mutation in human breast cancers may be a gain-of-function with respect to driving a more basal and/or metaplastic phenotype contributing to this highest mortality subtype of breast cancers (high grade/ Luminal B-type ER+ carcinomas). Citation Format: H. Mori, H. Moon, Q. Chen, A. Patino, K. Ramamurthy, J. Choi, J. D. McPherson, R. Cardiff, J. Snyder, A. D. Borowsky. Adaptive selection of p53 mutation metaplastic phenotypes in estrogen-independent progression of ER+ tumors: A mechanism for acquired resistance to hormonal therapy. [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-12.