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.