Metastatic HR+ HER2- breast cancer is an intractable disease that resists to the first-line treatment based on the combination of CDK4/6 inhibitor and hormone therapy (HT). To identify targets that further increase palbociclib-HT efficacy, we utilized biopsies from cancer patients who showed recurrence after treatment, HR+HER2- luminal cancer cells sensitive and resistant to the palbociclib-HT. Proteomic analysis of human samples revealed an upregulation of the oxidative stress-triggered proteasome subunit alpha7 (PSMA7) in metastatic relapses in different organs after patient's resistance to palbociclib-HT combination.