Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines

Natascia Marino, Joshua W. Collins, Changyu Shen, Natasha J. Caplen, Anand S. Merchant, Yesim Polar, Chirayu P. Goswami, Takashi Hoshino, Yongzhen Qian, George W. Sledge, Patricia S. Steeg

Research output: Contribution to journalArticle

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Abstract

Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47–62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.

Original languageEnglish
Pages (from-to)771-786
Number of pages16
JournalClinical and Experimental Metastasis
Volume31
Issue number7
DOIs
StatePublished - Oct 15 2014

Fingerprint

Tumor Suppressor Genes
Breast Neoplasms
Gene Expression
Cell Line
Type 5 Cyclic Nucleotide Phosphodiesterases
Neoplasm Metastasis
Small Interfering RNA
Genes
Mitogen-Activated Protein Kinase 14
Down-Regulation
Clone Cells
Gene Expression Profiling
Neoplasms
Theoretical Models
Cell Proliferation
Lung
Enzymes

Keywords

  • Bioinformatics
  • Breast cancer
  • Gene expression profiling
  • Metastasis
  • Metastasis suppressor genes
  • PDE5A

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines. / Marino, Natascia; Collins, Joshua W.; Shen, Changyu; Caplen, Natasha J.; Merchant, Anand S.; Polar, Yesim; Goswami, Chirayu P.; Hoshino, Takashi; Qian, Yongzhen; Sledge, George W.; Steeg, Patricia S.

In: Clinical and Experimental Metastasis, Vol. 31, No. 7, 15.10.2014, p. 771-786.

Research output: Contribution to journalArticle

Marino, N, Collins, JW, Shen, C, Caplen, NJ, Merchant, AS, Polar, Y, Goswami, CP, Hoshino, T, Qian, Y, Sledge, GW & Steeg, PS 2014, 'Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines', Clinical and Experimental Metastasis, vol. 31, no. 7, pp. 771-786. https://doi.org/10.1007/s10585-014-9667-0
Marino, Natascia ; Collins, Joshua W. ; Shen, Changyu ; Caplen, Natasha J. ; Merchant, Anand S. ; Polar, Yesim ; Goswami, Chirayu P. ; Hoshino, Takashi ; Qian, Yongzhen ; Sledge, George W. ; Steeg, Patricia S. / Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines. In: Clinical and Experimental Metastasis. 2014 ; Vol. 31, No. 7. pp. 771-786.
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abstract = "Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 {\%} compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47–62 {\%} fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.",
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AU - Polar, Yesim

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