However, due to the increased lactate production and excretion, the pHe is reduced to 6.5–7.1, while the pHi becomes slightly alkaline (≥7.2) in tumor cells, which is beneficial for tumor cell growth and metastasis.[29, 30, 31] The altered expression of some key proteins is proved to be responsible for the pH change in tumor cells, including Na+/H+ exchanger 1 (NHE1), Vacuolar H+ ATPases (V‐ATPases), and CAs.[29] We demonstrated here that CA12, a member in the CA protein family, is critical for maintaining the pH homeostasis and promoting the malignant phenotypes of ER+ breast cancer cells. The gene discussed is ESR1; the disease is breast carcinoma.