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Downloaded from the NIH Phase I/II Neoadjuvant Trials Using Combined Celecoxib GDC Data Portal ( Tian et al. Breast Cancer Research (2021) 23:23 https://doi.org/10.1186/s13058-021-01401-2 RESEARCH ARTICLE Open Access Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition Jun Tian, Vivian Wang, Ni Wang, Baharak Khadang, Julien Boudreault, Khldoun Bakdounes, Suhad Ali and Jean-Jacques Lebrun* Abstract Background: Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors. Methods: By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC. Results: We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo. Conclusions: Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment. Keywords: COX-2, Celecoxib, Breast cancer, TNBC, Drug resistance, MGFE8, KLK5/7 Background their aggressive clinical features and lack of specific mo- Triple negative breast cancers (TNBCs) account for lecular targets [2]. TNBC treatments using chemother- around 15% of all breast cancers and are pathologically apy and radiotherapy show limited therapeutic benefits, characterized by the negative expression of estrogen re- with the majority of patients still at high risk of relapse ceptor (ER) and progesterone receptor (PR) as well as and development of distant metastasis [3]. Therefore, ef- the aberrant expression of human epidermal growth fac- forts are needed to develop new therapeutic options with tor receptor 2 (HER2) [1]. TNBCs exhibit poor progno- long-lasting clinical responses for these deadly tumors. sis compared with other breast cancer subtypes due to Cyclooxygenase 2 (COX-2) is a key enzyme that cata- lyzes prostaglandins formation from arachidonic acid and is aberrantly expressed in various types of cancers, * Correspondence: [email protected] Department of Medicine, McGill University Health Center, Cancer Research including those of the breast [4–6]. COX-2 over- Program, 1001 Decarie Blvd, Bloc E, Suite E02.6224, Montreal, QC H4A 3J1, expression is found in 40% of invasive breast carcinoma Canada © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Tian et al. Breast Cancer Research (2021) 23:23 Page 2 of 18 cases and is associated with poor prognosis and tumor these genes (TPM4, RGS2, SERPINB5, MFGE8, KLK5, progression [7, 8]. Several studies using pre-clinical ID4) as potent regulators of lung colonization in preclin- models have demonstrated the involvement of COX-2/ ical TNBC model. Furthermore, we found MFGE8, Prostaglandin E2 (PGE2) pathway in various steps dur- KLK5, and KLK7 knockout (KO) to restore celecoxib ing breast cancer progression, including primary tumor sensitivity in TNBC cells leading to marked reductions growth [9], metastasis [10, 11], angiogenesis [12], and in primary tumor growth. Taken together, these results immune evasion [13]. Moreover, we recently found provide important rationale for developing COX-2 COX-2 to be highly expressed in TNBC tumors and its inhibitor-based combination therapies for breast cancer expression to correlate with poor overall survival (OS) patients, aiming at increasing/restoring the effectiveness and distant metastasis-free survival (DMFS) rates [14]. of COX-2 inhibitors in breast cancer patients. We further showed that COX-2 regulates the self- renewal capacity and expansion of breast cancer stem Methods cells, highlighting COX-2 as a very promising thera- Selection of patient data peutic target for TNBCs [14]. The TCGA data used in this study are derived from Selective COX-2 inhibitors (i.e., celecoxib; brand name Breast Invasive Carcinoma (TCGA, provisional) dataset Celebrex) are being used to treat patients with osteo- comprising 1108 samples [26, 27]. TNBC samples were arthritis and adult rheumatoid arthritis. Their safe use manually selected from the dataset based on the IHC has been further illustrated by low associated risk factors status of ER, PR, and HER2. Patients with a COX-2 for gastrointestinal and cardiovascular adverse events, mRNA z-score greater than + 1 (COX-2 high) or less compared with nonsteroidal anti-inflammatory drugs than − 0.25 (COX-2 low) compared with the overall dis- (NSAIDs) [15]. Interestingly, several preclinical studies tribution were selected for comparison using cBioPortal in breast cancer showed the use of selective COX-2 in- for Cancer Genomics online application (https://www. hibitors (celecoxib, rofecoxib, etodolac) could efficiently cbioportal.org/). Genome-wide RNA-sequencing data of block breast tumor growth and metastasis [16–22]. Early these patients were then downloaded from the NIH phase I/II neoadjuvant trials using combined celecoxib GDC data portal (https://portal.gdc.cancer.gov/). In all and aromatase inhibitors in the treatment of locally ad- cases, the normalized Fragments Per Kilobase of tran- vanced and metastatic breast cancers demonstrated re- script per Million mapped reads (FPKM) values of more ductions in breast tumor size and area [23, 24]. than 67,000 genes were downloaded and used for further However, a recent phase III, multicenter, double-blind, data analysis. randomized trial of celecoxib vs placebo in primary breast cancer patients (REACT trial) showed no benefit Differential expression gene analysis in delaying time to progression or overall survival [25]. Human mRNA expression data were loaded for each pa- These findings highlight the importance of addressing tient into a single spreadsheet and uploaded to the Gen- the underlying mechanisms that likely contributed to re- ePattern web software suite run by the Broad Institute. sistance to COX-2 inhibition in breast cancer. Thus, to Patient data were analyzed for differential gene expres- address this unmet clinical need, a better understanding sion using the ComparativeMarkerSelection tool com- of the molecular mechanisms and genes contributing to paring COX-2-high and COX-2-low patients. This tool celecoxib sensitivity/resistance in breast cancer is clearly uses a moderated t test to make pairwise comparisons warranted. Identification of such genes will allow for re- within the dataset and select for differentially enriched fined, more specific choice of biomarkers and patient genes. The genes were ranked based on their t-test value stratification, ultimately leading to better therapeutic and several filters (fold change >1.5, p value <0.05, t-test outcomes for TNBC patients. >2 or <−2, FDR <0.35) were applied to further select the With the ever-increasing release of large breast cancer significant differentially expressed genes. The resulted patient datasets, a wealth of patient data, including top 103 differentially expressed genes were then hier- tumor genomic and transcriptomic profiles as well as pa- archically clustered using the HierarchicalClustering tool tient clinical information have become available for data on the GenePattern web application. Pairwise average mining. In this study, we employed a systematic in silico linkage clustering with Pearson’s correlation coefficient approach to identify COX-2-associated genes and their was used to measure the similarity. clinical value in TNBC patients. This led us to define 10 candidate genes with high potential to (1) promote Selection of candidate genes TNBC tumorigenesis and (2) resistance to COX-2 inhib- The 43 DEGs enriched in COX-2-high TNBC patients itors. Further functional in vitro and in vivo validation of were analyzed for their genetic alteration rate (gene copy these candidate genes using CRISPR/Cas9-mediated
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