By using the two long-term estrogen deprivation (LTED) derivatives generating from MCF-7 and T47D, we found that the downregulation of serine protease inhibitor serpin family A member 3 (SERPINA3), a member of the serine-protease inhibitor family, could induce endocrine-resistance through regulating HDAC3 activity in ER+ breast cancer. The gene discussed is ESR1; the disease is breast cancer.