Transcriptome analysis of luminal breast cancer reveals a role for LOL in tumor progression and tamoxifen resistance.

Abstract

Luminal breast cancer (BC) has a sustained risk of late disease recurrence and death. Considerable numbers of patients suffer from antiendocrine therapy resistance. Here, we identified a novel lncRNA whose expression is high in breast cancer and especially higher in luminal breast cancer, dubbed LOL (lncRNA of luminal), that acts as a natural sponge for let-7 microRNAs to regulate tumor growth and tamoxifen resistance. LOL overexpression in parental MCF-7 cells exhibited a proliferative advantage in the addition of tamoxifen than negative control. Knocking down LOL in TamR MCF-7 cells, recovered the sensitivity of cells to tamoxifen. Strikingly, we demonstrated that LOL is transcribed from a genomic locus of an enhancer to maintain its high expression in luminal BC and that it is extremely sensitive to enhancer-regulating factors, such as ZMYND8 and BRD4. Estrogen deprivation or ERα signaling pathway blockage can further stimulate LOL expression, which can promote tumor progression. Clinical analysis of 374 luminal breast cancer samples indicated that LOL is an independent prognostic factor for poor survival in luminal BC. In conclusion, targeting LOL using preclinical/clinical drugs, such as BRD4 inhibitors, may represent a promising approach to inhibit luminal breast cancer progression and tamoxifen resistance.

• Authors: Wei Sun, Xiaoen Xu, Yizhou Jiang, Xi Jin, Ping Zhou, Yirong Liu, Yajie Guo, Ding Ma, Wenjia Zuo, Shenglin Huang, Xianghuo He, Zhiming Shao
• Journal: International journal of cancer (Int J Cancer) Vol. 145 Issue 3 Pg. 842-856 (08 01 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30720865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 UICC.

Chemical References

• Antineoplastic Agents, Hormonal
• MicroRNAs
• RNA, Long Noncoding
• mirnlet7 microRNA, human
• Tamoxifen

Topics

• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Proliferation (physiology)
• Down-Regulation
• Drug Resistance, Neoplasm
• Female
• G1 Phase Cell Cycle Checkpoints
• Gene Expression Profiling
• Heterografts
• Humans
• MCF-7 Cells
• Mice
• Mice, Inbred BALB C
• MicroRNAs (genetics, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• S Phase
• Tamoxifen (pharmacology)