Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression

David G. Burbee, Eva Forgacs, Sabine Zöchbauer-Müller, Latha Shivakumar, Kwun Fong, Boning Gao, Dwight Randle, Masashi Kondo, Arvind Virmani, Scott Bader, Yoshitaka Sekido, Farida Latif, Sara Milchgrub, Shinichi Toyooka, Adi F. Gazdar, Michael I. Lerman, Eugene Zabarovsky, Michael White, John D. Minna

Research output: Contribution to journalArticle

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Abstract

Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P = .046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.

Original languageEnglish
Pages (from-to)691-699
Number of pages9
JournalJournal of the National Cancer Institute
Volume93
Issue number9
DOIs
Publication statusPublished - 02-05-2001

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Epigenomics
Lung Neoplasms
Breast Neoplasms
Phenotype
Cell Line
Small Cell Lung Carcinoma
Non-Small Cell Lung Carcinoma
Tumor Suppressor Genes
Lung
Genetic Promoter Regions
Methylation
Breast
Complementary DNA
Cell Culture Techniques
Chromosomes
Alleles
Messenger RNA
Survival
Growth
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Burbee, D. G., Forgacs, E., Zöchbauer-Müller, S., Shivakumar, L., Fong, K., Gao, B., ... Minna, J. D. (2001). Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. Journal of the National Cancer Institute, 93(9), 691-699. https://doi.org/10.1093/jnci/93.9.691
Burbee, David G. ; Forgacs, Eva ; Zöchbauer-Müller, Sabine ; Shivakumar, Latha ; Fong, Kwun ; Gao, Boning ; Randle, Dwight ; Kondo, Masashi ; Virmani, Arvind ; Bader, Scott ; Sekido, Yoshitaka ; Latif, Farida ; Milchgrub, Sara ; Toyooka, Shinichi ; Gazdar, Adi F. ; Lerman, Michael I. ; Zabarovsky, Eugene ; White, Michael ; Minna, John D. / Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. In: Journal of the National Cancer Institute. 2001 ; Vol. 93, No. 9. pp. 691-699.
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abstract = "Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100{\%} of the SCLC, in 65{\%} of the NSCLC, or in 60{\%} of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100{\%} of SCLC, in 63{\%} of NSCLC, in 64{\%} of breast cancer lines, in 30{\%} of primary NSCLCs, and in 49{\%} of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P = .046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.",
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Burbee, DG, Forgacs, E, Zöchbauer-Müller, S, Shivakumar, L, Fong, K, Gao, B, Randle, D, Kondo, M, Virmani, A, Bader, S, Sekido, Y, Latif, F, Milchgrub, S, Toyooka, S, Gazdar, AF, Lerman, MI, Zabarovsky, E, White, M & Minna, JD 2001, 'Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression', Journal of the National Cancer Institute, vol. 93, no. 9, pp. 691-699. https://doi.org/10.1093/jnci/93.9.691

Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. / Burbee, David G.; Forgacs, Eva; Zöchbauer-Müller, Sabine; Shivakumar, Latha; Fong, Kwun; Gao, Boning; Randle, Dwight; Kondo, Masashi; Virmani, Arvind; Bader, Scott; Sekido, Yoshitaka; Latif, Farida; Milchgrub, Sara; Toyooka, Shinichi; Gazdar, Adi F.; Lerman, Michael I.; Zabarovsky, Eugene; White, Michael; Minna, John D.

In: Journal of the National Cancer Institute, Vol. 93, No. 9, 02.05.2001, p. 691-699.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression

AU - Burbee, David G.

AU - Forgacs, Eva

AU - Zöchbauer-Müller, Sabine

AU - Shivakumar, Latha

AU - Fong, Kwun

AU - Gao, Boning

AU - Randle, Dwight

AU - Kondo, Masashi

AU - Virmani, Arvind

AU - Bader, Scott

AU - Sekido, Yoshitaka

AU - Latif, Farida

AU - Milchgrub, Sara

AU - Toyooka, Shinichi

AU - Gazdar, Adi F.

AU - Lerman, Michael I.

AU - Zabarovsky, Eugene

AU - White, Michael

AU - Minna, John D.

PY - 2001/5/2

Y1 - 2001/5/2

N2 - Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P = .046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.

AB - Background: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. Methods: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. Results: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P = .046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. Conclusion: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.

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