In our study herein, we show that both SAM-cooperative (e.g., pemrametostat) and SAM-competitive (e.g., JNJ-64619178) PRMT5i block growth of ER+/RB-deficient breast cancer in vitro and/or in vivo, thus providing a rationale for the testing of first generation PRMT5i in patients with CDK4/6i-refractory breast cancers. The gene discussed is ESR1; the disease is breast carcinoma.