Estrogen‐Induced LncRNA, LINC02568, Promotes Estrogen Receptor‐Positive Breast Cancer Development and Drug Resistance Through Both In Trans and In Cis Mechanisms

Abstract Endocrine therapy is the frontline treatment for estrogen receptor (ER) positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy drugs remain as a major challenge in the clinic. Here, this work identifies an estrogen‐induced lncRNA, LINC02568, which is highly expressed in ER‐positive breast cancer and functional important in cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy drug resistance. Mechanically, this work demonstrates that LINC02568 regulates estrogen/ERα‐induced gene transcriptional activation in trans by stabilizing ESR1 mRNA through sponging miR‐1233‐5p in the cytoplasm. Meanwhile, LINC02568 contributes to tumor‐specific pH homeostasis by regulating carbonic anhydrase CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy drug resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER‐positive breast cancer cell growth in vitro and tumorigenesis in vivo. Furthermore, combination treatment with ASO targeting LINC02568 and endocrine therapy drugs or CA12 inhibitor U‐104 exhibits synergistic effects on tumor growth. Taken together, the findings reveal the dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER‐positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in the clinic.