Our results demonstrated that exposure to hypoxia causes the loss of function of vacuolar protein sorting-associated protein VPS4B, which is involved in maintaining the fidelity of multivesicular body (MVB) maturation, resulting in increased breast cancer cell anchorage-independent growth and resistance to anti-EGFR, anti-MEK and genotoxicity induction treatment. Here, VPS4B is linked to breast carcinoma.