Adaptive selection of p53 mutation metaplastic phenotypes in estrogen-independent progression of ER+ tumors: A mechanism for acquired resistance to hormonal therapy.
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-Stat1 tm1Rds ( 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. Here, data shows that 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. 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. 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.
