ESR1-Stabilizing Long Noncoding RNA TMPO-AS1 Promotes Hormone-Refractory Breast Cancer Progression

ABSTRACT

Acquired endocrine therapy resistance is a significant clinical problem for breast cancer patients. In recent years, increasing attention has been paid to long noncoding RNA (lncRNA) as a critical modulator for cancer progression. Based on RNA-sequencing data of breast invasive carcinomas in The Cancer Genome Atlas database, we identified thymopoietin antisense transcript 1 (TMPO-AS1) as a functional lncRNA that significantly correlates with proliferative biomarkers. TMPO-AS1 positivity analyzed by in situ hybridization significantly correlates with poor prognosis of breast cancer patients. TMPO-AS1 expression was upregulated in endocrine therapy-resistant MCF-7 cells compared with levels in parental cells and was estrogen inducible. Gain and loss of TMPO-AS1 experiments showed that TMPO-AS1 promotes the proliferation and viability of estrogen receptor (ER)-positive breast cancer cells in vitro and in vivo. Global expression analysis using a microarray demonstrated that TMPO-AS1 is closely associated with the estrogen signaling pathway. TMPO-AS1 could positively regulate estrogen receptor 1 (ESR1) mRNA expression by stabilizing ESR1 mRNA through interaction with ESR1 mRNA. Enhanced expression of ESR1 mRNA by TMPO-AS1 could play a critical role in the proliferation of ER-positive breast cancer. Our findings provide a new insight into the understanding of molecular mechanisms underlying hormone-dependent breast cancer progression and endocrine resistance.

KEYWORDS:

• RNA stability
• breast cancer
• estrogen
• long noncoding RNA

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00261-19.

ACKNOWLEDGMENTS

We thank Tomoko Suzuki, Miwa Fujitani, and Noriko Sasaki for their technical assistance and Kenichi Takayama for critical discussion and advice.

This work was supported in part by the Support Project of the Strategic Research Centers in Private Universities (to S.I. and K.H.-I.) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan; by the Practical Research for Innovative Cancer Control (JP18ck0106194 to K.I.) and the Project for Cancer Research and Therapeutic Evolution (P-CREATE to S.I.) from the Japan Agency for Medical Research and Development, AMED; by Grants in Aid for Scientific Research (B) (17H04205 to K.H.-I.), for Challenging Exploratory Research (16K15496 to K.H.-I.), for Young Scientists (B) (17K18061 to Y.M.), and for a JSPS fellow (18J00252 to Y.M.) from the Japan Society for the Promotion of Science (JSPS), Japan; and by the Takeda Science Foundation (to S.I.).