<scp>LHPP</scp>‐<scp>P38 MAPK</scp>/<scp>ERK</scp>‐<scp>ETS1</scp> Axis Negative Feedback Signaling Restrains Progression in Breast Cancer

Invasion and metastasis are major causes of mortality in breast cancer (BRCA) patients. LHPP, known for its tumor-suppressive effects, has an undefined role in BRCA. We found reduced LHPP protein in BRCA tissues, with lower levels correlating with poor patient outcomes. In vitro studies show LHPP inhibits BRCA cell proliferation, migration, invasion, and stemness. In vivo xenograft models support LHPP's role in curbing tumorigenesis and lung metastasis. Mechanistically, LHPP interacts with ERK and P38 MAPK, leading to their dephosphorylation and suppression of the MAPK pathway. We also reveal ETS1, a MAPK effector, repressing LHPP mRNA transcription, suggesting a LHPP-P38 MAPK/ERK-ETS1 negative feedback loop as a key regulatory mechanism in controlling BRCA invasion and metastasis.