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Novel Mechanistic Targets of Forkhead Box Q1 Transcription Factor in Human Breast Cancer Cells

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Novel Mechanistic Targets of Forkhead Box Q1 Transcription Factor in Human Breast Cancer Cells bioRxiv preprint doi: https://doi.org/10.1101/2020.05.26.117176; this version posted May 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Novel mechanistic targets of Forkhead box Q1 transcription factor in human breast cancer cells Su-Hyeong Kim*,1, Eun-Ryeong Hahm*,1, Krishna B. Singh*, and Shivendra V. Singh*,¶,2 From the *Department of Pharmacology & Chemical Biology, and ¶UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Running Title: Role of FoxQ1 in breast cancer 2To whom correspondence should be addressed: 2.32A Hillman Cancer Center Research Pavilion, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3263; Fax: 412-623-7828; E-mail: [email protected] Keywords: Breast Cancer, FoxQ1, Cell Cycle, Interleukin-1α, Interleukin-8 The transcription factor forkhead box Q1 analysis. FoxQ1 overexpression resulted (FoxQ1), which is overexpressed in in downregulation of genes associated different solid tumors, has emerged as a with cell cycle checkpoints, M phase, and key player in the pathogenesis of breast cellular response to stress/external stimuli cancer by regulating epithelial- as evidenced from the Reactome pathway mesenchymal transition, maintenance of analysis. Consequently, FoxQ1 cancer-stem like cells, and metastasis. overexpression resulted in S, G2M and However, the mechanism underlying mitotic arrest in basal-like SUM159 and oncogenic function of FoxQ1 is still not HMLE cells, but not in luminal-type fully understood. In this study, we MCF-7 cells. There were differences in compared the RNA-seq data from FoxQ1 expression of cell cycle-associated overexpressing SUM159 cells with that of proteins between FoxQ1 overexpressing empty vector-transfected control (EV) SUM159 and MCF-7 cells. Finally, we cells to identify novel mechanistic targets show for the first time that FoxQ1 is a of this transcription factor. Consistent direct transcriptional regulator of with published results in basal-like interleukin (IL)-1α, IL-8, and vascular subtype, immunohistochemistry revealed endothelial growth factor in breast cancer upregulation of FoxQ1 protein in cells. Chromatin immunoprecipitation luminal-type human breast cancer tissue revealed FoxQ1 occupancy at the microarrays when compared to normal promoters of IL-1α, IL-8, and VEGF. In mammary tissues. Many previously conclusion, the present study reports reported transcriptional targets of FoxQ1 novel mechanistic targets of FoxQ1 in (e.g., E-cadherin, N-cadherin, fibronectin human breast cancer cells. 1, etc.) were verified from the RNA-Seq challenging aspect in clinical management Introduction of breast cancer relates to molecular Breast cancer remains an alarming heterogeneity of the disease that is health concern for women worldwide characterized by distinct gene expression reflected by more than 40,000 deaths each signatures and overexpression of driver year in the United States alone (1). A oncogenic proteins (2-5). Majority of the 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.05.26.117176; this version posted May 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. invasive mammary ductal carcinomas are immortalized by hTERT and SV40 large T broadly grouped into four subtypes, antigen (HMLER) also promoted stem-like including luminal A type [estrogen receptor phenotype characterized by increased positive (ER+3), progesterone receptor mammosphere multiplicity (8). Importantly, positive (PR+), and human epidermal suppression of FoxQ1 expression in MDA- growth factor receptor 2 positive (HER2+)], MB-231 cells resulted in increased active luminal B type (ER+/PR+/HER2-), HER2- caspase-3 level in response to treatment with enriched, and basal-like (2,3). Nearly 75% several chemotherapy drugs, including 5- of basal-like breast tumors are triple- fluorouracil, taxol, and camptothecin (8). negative due to lack of ER, PR, and HER2 Transcriptional inactivation of E-cadherin expression (6). Further characterization of by FoxQ1 overexpression was also the disease subtype-independent oncogenic demonstrated in this study (8). dependencies in breast cancer is necessary to Subsequently, platelet-derived growth factor identify novel druggable targets to broaden receptor α/β were identified as additional therapeutic options for different subtypes of downstream targets of FoxQ1 in promotion breast cancer. of breast cancer stem cell-like phenotype as well as chemoresistance (9). We have also The transcription factor forkhead box shown previously that FoxQ1 promotes Q1 (FoxQ1) has recently emerged as a key breast cancer stem-like phenotype in a player in the pathogenesis of breast cancer luminal-type (MCF-7) and a basal-like (7-9). Zhang et al. (7) were the first to (SUM159) cell line by causing direct demonstrate a role for FoxQ1 in epithelial- transcriptional repression of the tumor mesenchymal transition (EMT) in breast suppressor Dachshund homolog 1 (DACH1) cancer metastasis using a cross-species gene (10). expression profiling strategy. Forced expression of FoxQ1 in a human mammary Published studies thus far clearly epithelial cell line (HMLE) and EpRas cells indicate that FoxQ1 regulates expression of increased their ability to migrate and invade multiple cancer-relevant genes to promote in vitro, and these effects were reversible by cell invasion/migration, stem-like knockdown of this protein in 4T1 mouse phenotype, and chemotherapy resistance in mammary carcinoma cells (7). Moreover, vitro and metastasis in vivo in breast cancer FoxQ1 overexpressing EpRas cells exhibited cell lines, but the possibility of additional increased propensity for pulmonary functionally important targets of this metastasis in vivo (7). Promotion of the transcription factor can’t be fully ignored. EMT phenotype by FoxQ1 overexpression To address this question, we compared was due to direct repression of E-cadherin RNA-Seq data from FoxQ1 overexpressing protein expression (7). In another study, SUM159 (hereafter abbreviated as FoxQ1 FoxQ1 expression was shown to correlate cells) cells with that of empty vector with high-grade basal-like breast cancers transfected control cells (hereafter and associated with poor clinical outcomes abbreviated as EV cells) to identify its (8). RNA interference of FoxQ1 in a highly additional mechanistic targets. The present invasive basal-like human breast cancer cell study reveals novel downstream targets of line (MDA-MB-231) attenuated EMT FoxQ1 in breast cancer including cell cycle phenotype and decreased its invasion ability control, interleukin (IL)-1α, IL-8, and (8). Ectopic expression of FoxQ1 in a vascular endothelial growth factor (VEGF). human mammary epithelial cell line 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.05.26.117176; this version posted May 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Results Volcano plot in Fig. 1D depicts distribution of differentially expressed genes between FoxQ1 protein is overexpressed in luminal- FoxQ1 overexpressing SUM159 cells and type human breast cancers compared to EV cells with a threshold cut-off of 1.3-fold normal mammary tissues change in expression and at an adjusted p We have shown previously that the value of < 0.05 (Fig. 1D). The heatmaps of level of FoxQ1 protein and mRNA is three replicates of each group exhibiting relatively higher in basal-like human breast highly consistent transcriptional changes are cancer cell lines (e.g., MDA-MB-231) in shown in Fig. 1E. The Venn diagram shown comparison with a normal mammary in Fig. 1F shows unique and overlapping epithelial cell line (MCF-10A) or luminal- gene expression between FoxQ1 type cells (e.g., MCF-7 and MDA-MB-361) overexpressing SUM159 cells and EV cells. (10). Moreover, basal-like human breast cancers exhibited higher level of FoxQ1 Kyoto encyclopedia of genes and genomes protein when compared to normal mammary (KEGG) pathway analysis tissues (10). Initially, we compared the The top 5 pathways with upregulated expression of FoxQ1 gene expression in genes from the KEGG analysis included white versus black breast cancer patients and pathways in cancer (84 genes), mitogen- between ductal and lobular carcinomas in activated protein kinase signaling (56 breast cancer TCGA dataset. The expression genes), regulation of actin cytoskeleton (49 of FoxQ1 was marginally but significantly genes), focal adhesion (50 genes), and axon higher in the tumors of black women when guidance (37 genes) (Fig. 2A). The top 5 compared to white women (Fig. 1A). On the pathways with downregulated genes from other hand, the expression of FoxQ1 was the KEGG pathway analysis were cell cycle comparable between ductal and lobular (41 genes), oocyte meiosis (38 genes), breast cancers (Fig. 1A). In this study, we progesterone-mediated oocyte maturation also examined the expression of FoxQ1 (29 genes), lysine degradation (18 genes), protein in tissue microarrays consisting of and protein processing in endoplasmic luminal-type breast cancers and normal reticulum (46 genes) (Fig. 2B). mammary tissues. Fig. 1B shows immunohistochemical staining for FoxQ1 in The gene ontology (GO) and Reactome representative normal mammary tissues and pathway analyses
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