A PML1-CCL5-PI3K/MAPK feedback loop governs survival of endocrine-resistant breast cancer cells
PML1–CCL5–HBEGF positive feedback loop drives PI3K and MAPK signaling and sustains endocrine therapy resistance in 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.
Understanding how PML1 drives endocrine resistance can inform strategies to overcome therapy failure in breast cancer patients.
Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.
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