A combined connectivity mapping and pharmacoepidemiology approach to identify existing medications with breast cancer causing or preventing properties

Busby, John; Murray, Liam; Mills, Ken; Zhang, Shudong; Liberante, Fabio G.; Cardwell, Christopher

doi:10.1002/pds.4345

Cited by 13 publications

(12 citation statements)

References 45 publications

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“…In line with our idea, pharmacological targeting of this collagen-epigenetic axis with budesonide, identified in this study, inhibits the metastatic dissemination of SUM159 cells by preventing mesenchymal-transition. Interestingly, budesonide, has been very recently identified in a combined connectivity mapping and pharmacoepidemiological approach as a drug with potential breast cancer-preventing properties (29). Moreover, budesonide is universally employed to treat asthma, and asthma was recently associated with reduced risk of developing pancreatic ductal adenocarcinoma (30).…”

Section: Discussionmentioning

confidence: 99%

Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

et al. 2019

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Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic budesonide, blocked metastatic dissemination of breast cancer cells in vivo by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. Significance: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.

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Section: Discussionmentioning

confidence: 99%

Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

et al. 2019

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“…Interestingly, asthmatic patients under longterm treatment with Budesonide show reduced risk to develop pancreatic ductal adenocarcinoma (137). Moreover, Budesonide has been recently identified, using a combined connectivity mapping and pharmacoepidemiology approach, as a potential treatment for preventing breast cancer (138). Finally, by blocking collagen synthesis and hydroxylation in the ER, Budesonide increases VitC availability in the nucleus, resulting in epigenetic remodeling, i.e., a global reduction of DNA and histone methylation levels (57), thus showing its potential for targeting cancer cell plasticity and identity.…”

Section: Potential Therapeutic Strategies Targeting Proline Metabolismentioning

confidence: 99%

Proline Metabolism in Tumor Growth and Metastatic Progression

et al. 2020

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Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist therapy. Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-essential amino acids in this complex scenario. Here we discuss the impact of proline metabolism in cancer development and progression, with particular emphasis on the enzymes involved in proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how proline availability influences collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby proline availability generates a cycle based on collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic cancers.

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“…We also identified seven potential target drugs: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU-1025, bumetanide and DQNLAOWBTJPFKL-PKZXCIMASA-N of LINC00668 in HCC via the Connectivity Map. The Connectivity Map database can provide a unique method of drug development through the comparison of potential chemical compounds that can be used to treat diseases, including tumors, and it has been accepted by several researchers (51,52). Xiao et al (53) utilized expression profile chip data and a Connectivity Map to explore the molecular mechanisms of Hirschsprung's disease and candidate target drugs.…”

Section: Discussionmentioning

confidence: 99%

Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor initiation, progression and prognosis. The present study aimed to explore the association between long noncoding RNA LINC00668 and its co-expression correlated protein-coding genes (PCGs) in HCC. Data of 370 HCC patients from The Cancer Genome Atlas database were used for analysis. LINC00668 and its top 10 PCGs were selected to determine their diagnostic and prognostic value. Molecular mechanisms were explored to identify metabolic processes that LINC00668 and its PCGs are involved in. Prognosis-related clinical factors and PCGs were used to construct a nomogram for predicting prognosis in HCC. A Connectivity Map was constructed to identify candidate target drugs for HCC. The top 10 PCGs identified were: Pyrimidineregic receptor P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), family with sequence similarity 86 member C1 (FAM86C1), tudor domain containing 5 (TDRD5), ferritin light chain (FTL), stratifin (SFN), nucleolar complex associated 2 homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain containing (LZIC). FAM86C1, CTAG2 and SFN had significant diagnostic value for HCC (total area under the curve ≥0.7, P≤0.05); LINC00668, FAM86C1, TDRD5, FTL and SFN were of significant prognostic value for HCC (all P≤0.05). Investigation into the molecular mechanism indicated that LINC00668 affects cell division, cell cycle, mitotic nuclear division, and drug metabolism cytochrome P450 (all P≤0.05). The Connectivity Map identified seven candidate target drugs for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU-1025, bumetanide, and DQNLAOWBTJPFKL-PKZXCIMASA-N (all P≤0.05). Our findings indicated that LINC00668 may function as an oncogene and its overexpression indicates poor prognosis of HCC. FAM86C1, CTAG2 and SFN are of diagnostic significance, while FAM86C1, TDRD5, FTL and SFN are of prognostic significance for HCC.

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A combined connectivity mapping and pharmacoepidemiology approach to identify existing medications with breast cancer causing or preventing properties

Cited by 13 publications

References 45 publications

Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

Proline Metabolism in Tumor Growth and Metastatic Progression

Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma

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