AUTHOR=Hassani Bita , Taheri Mohammad , Asgari Yazdan , Zekri Ali , Sattari Ali , Ghafouri-Fard Soudeh , Pouresmaeili Farkhondeh 

TITLE=Expression Analysis of Long Non-Coding RNAs Related With FOXM1, GATA3, FOXA1 and ESR1 in Breast Tissues

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.671418

DOI=10.3389/fonc.2021.671418

ISSN=2234-943X

ABSTRACT=<p>Breast cancer is the most common neoplasm among females. Estrogen receptor (ESR) signaling has a prominent impact in the pathogenesis of breast cancer. Among the transcription factors associated with ESR signaling, FOXM1, GATA3, FOXA1 and ESR1 have been suggested as a candidate in the pathogenesis of this neoplasm. In the current project, we have designed an <italic>in silico</italic> approach to find long non-coding RNAs (lncRNAs) that regulate these transcription factors. Then, we used clinical samples to carry out validation of our in silico findings. Our systems biology method led to the identification of <italic>APTR</italic>, <italic>AC144450.1</italic>, <italic>linc00663</italic>, <italic>ZNF337.AS1</italic>, and <italic>RAMP2.AS1</italic> lncRNAs. Subsequently, we assessed the expression of these genes in breast cancer tissues compared with the adjacent non-cancerous tissues (ANCTs). Expression of <italic>GATA3</italic> was significantly higher in breast cancer tissues compared with ANCTs (Ratio of mean expressions (RME) = 4.99, P value = 3.12E−04). Moreover, expression levels of <italic>APTR</italic>, <italic>AC144450.1</italic>, and <italic>ZNF337.AS1</italic> were elevated in breast cancer tissues compared with control tissues (RME = 2.27, P value = 5.40E−03; Ratio of mean expressions = 615.95, P value = 7.39E−19 and RME = 1.78, P value = 3.40E−02, respectively). On the other hand, the expression of <italic>RAMP2.AS1</italic> was lower in breast cancer tissues than controls (RME = 0.31, P value = 1.87E−03). Expression levels of <italic>FOXA1</italic>, <italic>ESR1</italic>, and <italic>FOXM1</italic> and <italic>linc00663</italic> were not significantly different between the two sets of samples. Expression of <italic>GATA3</italic> was significantly associated with stage (P value = 4.77E−02). Moreover, expressions of <italic>FOXA1</italic> and <italic>RAMP2.AS1</italic> were associated with the mitotic rate (P values = 2.18E−02 and 1.77E−02, respectively). Finally, expressions of <italic>FOXM1</italic> and <italic>ZNF337.AS1</italic> were associated with breastfeeding duration (P values = 3.88E−02 and 4.33E−02, respectively). Based on the area under receiver operating characteristics curves, <italic>AC144450.1</italic> had the optimal diagnostic power in differentiating between cancerous and non-cancerous tissues (AUC = 0.95, Sensitivity = 0.90, Specificity = 0.96). The combination of expression levels of all genes slightly increased the diagnostic power (AUC = 0.96). While there were several significant pairwise correlations between expression levels of genes in non-tumoral tissues, the most robust correlation was identified between <italic>linc00663</italic> and <italic>RAMP2.AS1</italic> (r = 0.61, P value = 3.08E−8). In the breast cancer tissues, the strongest correlations were reported between <italic>FOXM1</italic>/<italic>ZNF337.AS1</italic> and <italic>FOXM1</italic>/<italic>RAMP2.AS1</italic> pairs (r = 0.51, P value = 4.79E−5 and r = 0.51, P value = 6.39E−5, respectively). The current investigation suggests future assessment of the functional role of <italic>APTR</italic>, <italic>AC144450.1</italic> and <italic>ZNF337.AS1</italic> in the development of breast neoplasms.</p>