Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) interacts with estrogen receptor and predicted poor survival in breast cancer

Abstract

Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1), a lncRNA that was first recognized as a prognostic parameter for patient survival of stage I lung cancer, is up-regulated in multiple human malignancies, including breast cancer. However, the mechanism of its function remained elusive. In the current study, by examining MALAT1 expression on mRNA level, we demonstrated that compared with MCF10A, MALAT1 expression was up-regulated in the majority of breast cancer cell lines (9/12). In 26 pairs of estrogen receptor (ER)-positive breast cancer samples, MALAT1 expression was significantly up-regulated compared with adjacent normal tissues (P = 0.012). Furthermore, of 204 breast cancer patients, high MALAT1 expression was associated with positive ER (P = 0.023) and progesterone receptor (PR) (P = 0.024) status. Further analysis using TCGA database revealed that ER and its target genes PGR and CCND1, were overexpressed in MALAT1 altered group compared with unaltered group, both on the mRNA and protein level. Lastly, we verified MALAT1's prognostic value in breast cancer. At the cut-off value of 75%, MALAT1 was the only independent prognostic factor of recurrence-free survival (RFS) in ER-negative patients in a multivariate Cox regression model (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.02-7.83). MALAT1 overexpression was also associated with poor RFS in tamoxifen treated ER-positive breast cancer patients, which might serve as a potential biomarker to predict endocrine treatment sensitivity.

Keywords: MALAT1; breast cancer; estrogen receptor; long non-coding RNA.

Figure 1

(A) MALAT1 expression profile in 13 breast cell lines. Compared with the normal breast cell line MCF10A, MALAT1 expression was up-regulated in MDAMB436, MDAMB468, BT549, ZR751, MCF7, T47D, SKBR3, MDAMB231HM, and BT474; (B) MALAT1 expression was significantly up-regulated compared with adjacent normal tissues (P = 0.012) in ER-positive breast cancers.

Figure 2. MALAT1 correlated with ER and its downstream genes' expression

(A) MALAT1 was amplified or up-regulated in 7% of breast cancer cases; (B) MALAT1 and ER expression was moderately correlated on the mRNA level; (C) MALAT1 was related to ER expression on the mRNA and protein level; (D) and (E), MALAT1 was related to the expression of ER's target genes, PGR and CCND1, on the mRNA and protein level.

Figure 3. Survival analysis in breast cancer patients based on MALAT1 expression

(A) Recurrence-free survival based on low MALAT1 expression versus high MALAT1 expression in the ER-positive group; (B) Recurrence-free survival based on low MALAT1 expression versus high MALAT1 expression in the ER-negative group.

Figure 4. Survival analysis in tamoxifen treated ER-positive breast cancer patients based on MALAT1 expression

(A) Recurrence-free survival based on low MALAT1 expression versus high MALAT1 expression in a cohort of 57 patients in our institute; (B) Recurrence-free survival based on low MALAT1 expression versus high MALAT1 expression in Gyorffy's dataset of 161 patients.