A PML1-CCL5-PI3K/MAPK feedback loop governs survival of endocrine-resistant breast cancer cells

The mechanisms that mediate endocrine therapy resistance remain incompletely understood. We identified promyelocytic leukemia protein isoform 1 (PML1) as a central node of this resistance. We established a PML1 gene signature that strongly correlates with PI3K, MAPK, and endocrine resistance signatures across multiple patient cohorts, predicting poor clinical outcomes. Mechanistically, PML1 promotes a self-reinforcing survival circuit by inducing the expression of CCL5 and HBEGF, which activate PI3K and MAPK signaling in an autocrine/paracrine manner. Reciprocally, ERK activation stabilizes PML1 protein, whereas activated mTOR increases PML1 protein synthesis, thereby establishing a positive feedback loop that sustains cancer cell survival under therapeutic pressure. Paradoxically, selective ER degraders (SERDs) and modulators (SERMs) induce PML1 protein accumulation. Fulvestrant, a SERD, while inducing ER protein degradation, rapidly activates PI3K and MAPK pathways, driving PML1 protein accumulation. Consistently, we observed an inverse relationship between ER and PML protein levels. In therapy-sensitive wild-type ER cells with low basal PML1 levels and PI3K/MAPK activity, fulvestrant's ER-suppressive effects overcome drug-induced elevated PML1 and PI3K/MAPK activity, thereby maintaining therapeutic efficacy. In contrast, in therapy-resistant ER Y537S mutant cells or cells with PML gene amplification, fulvestrant-mediated amplification of constitutively hyperactive PML1-PI3K/MAPK feedback loops dominates over cytotoxic effects, resulting in enhanced cell survival. Notably, reducing PML1 levels through knockdown or arsenic trioxide (ATO), an FDA-approved PML1 degrader, disrupts this resistance circuit and restores endocrine sensitivity. Treatment of ATO resensitizes ER Y537S-bearing resistant tumors to endocrine therapy in xenograft models. These findings establish PML1 as a central hub of resistance, linking ER signaling to the activation of the PI3K/MAPK survival pathway.