Skip to content

Research at St Andrews

Morphologically Normal-Appearing Mammary Epithelial Cells Obtained from High-Risk Women Exhibit Methylation Silencing of INK4a/ARF.

Research output: Contribution to journalArticle

Author(s)

GR Bean, AD Bryson, PD Pilie, V Goldenberg, JC Baker, C Ibarra, DMU Brander, C Paisie, NR Case, M Gauthier, Paul Andrew Reynolds, E Dietz, J Ostrander, V Scott, LG Wilke, L Yee, BF Kimler, CJ Fabian, CM Zalles, G Broadwater & 2 others TD Tlsty, VL Seewaldt

School/Research organisations

Abstract

Purpose: p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin remodeling and DNA methylation. These data suggest that cells that lack p16(INK4a) activity would be at high risk for breast cancer development and may exhibit an increased frequency of DNA methylation events in early cancer.

Experimental Design: To test this hypothesis, the frequencies of INK4a/ARF promoter hypermethylation, as well as four additional selected loci, were tested in the initial random periareolar fine needle aspiration samples from 86 asymptomatic women at high risk for development of breast cancer, stratified using the Masood cytology index.

Results: INK4a/ARF promoter hypermethylation was observed throughout all early stages of intraepithelial neoplasia and, importantly, in morphologically normal-appearing mammary epithelial cells; 29 of 86 subjects showed INK4a/ARF promoter hype rmethylation in at least one breast. Importantly, INK4a/ARF promoter hype rmethylation was not associated with atypia, and the frequency of hypermethylation did not increase with increasing Masood cytology score. The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-beta 2, estrogen receptor-alpha, and breast cancer-associated 1 genes (P = 0.001).

Conclusions: Because INK4a/ARF promoter hype rmethylati on does not increase with age but increases with the frequency of other methylation events, we predict that INK4a/ARF promoter hypermethylation may serve as a marker of global methylation dysregulation.

Close

Details

Original languageEnglish
Pages (from-to)6834-6841
Number of pages8
JournalClinical Cancer Research
Volume13
DOIs
Publication statusPublished - 15 Nov 2007

    Research areas

  • FINE-NEEDLE-ASPIRATION, ABERRANT PROMOTER METHYLATION, CPG ISLAND METHYLATION, HUMAN BREAST-CANCER, DNA METHYLATION, IN-SITU, P16(INK4A), EXPRESSION, GENE, HETEROZYGOSITY

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Genome-scale CRISPR/Cas9 screen determines factors modulating sensitivity to ProTide NUC-1031

    Sarr, A., Bré, J., Um, I. H., Chan, T. H., Mullen, P., Harrison, D. J. & Reynolds, P. A., 21 May 2019, In : Scientific Reports. 9, 13 p., 7643.

    Research output: Contribution to journalArticle

  2. Glutaminase inhibition in renal cell carcinoma therapy

    Raczka, A. M. & Reynolds, P. A., 14 May 2019, In : Cancer Drug Resistance. 2, 9 p.

    Research output: Contribution to journalReview article

  3. Podocyte injury elicits loss and recovery of cellular forces

    Haley, K., Kronenberg, N. M., Liehm, P., Elshani, M., Bell, C., Harrison, D. J., Gather, M. C. & Reynolds, P. A., 27 Jun 2018, In : Science Advances. 4, 6, 9 p., eaap8030.

    Research output: Contribution to journalArticle

  4. Crumbs 3b promotes tight junctions in an ezrin-dependent manner in mammalian cells

    Tilston-Lunel, A. M., Haley, K., Schlecht, N., Wang, Y., Chatterton, A. L. D., Moleirinho, S. L., Watson, A., Hundal, H., Prystowsky, M., Gunn-Moore, F. J. & Reynolds, P. A., Oct 2016, In : Journal of Molecular Cell Biology. 8, 5, p. 439-455

    Research output: Contribution to journalArticle

  5. Willing to be involved in cancer

    Gunn-Moore, F. J., Tilston-Lunel, A. M. & Reynolds, P. A., 18 Jul 2016, In : Genes. 7, 7, 13 p., 37.

    Research output: Contribution to journalReview article

Related by journal

  1. Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer

    Stewart, G. D., O'Mahony, F., Laird, A., Eory, L., Lubbock, A., Mackay, A., Nanda, J., O'Donnell, M., Mullen, P., McNeill, A., Riddick, A., Berney, D., Bex, A., Aitchison, M., Overton, I. M., Harrison, D. J. & Powles, T., 2015, In : Clinical Cancer Research. In press

    Research output: Contribution to journalArticle

  2. The effect of VEGF targeted therapy on biomarker expression in sequential tissue from patients with metastatic clear cell renal cancer

    Sharpe, K., Stewart, G. D., Mackay, A., Van Neste, C., Rofe, C., Berney, D. M., Kayani, I., Bex, A., Wan, E., O'Mahony, F., O'Donnell, M., Chowdhury, S., Doshi, R., Ho Yen, C., Gerlinger, M., Baker, D., Smith, N. R., Davies, B. R., Sahdev, A., Boleti, E. & 7 others, de Meyer, T., Van Criekinge, W., Beltran, L., Lu, Y-J., Harrison, D., Reynolds, A. R. & Powles, T., 15 Dec 2013, In : Clinical Cancer Research. 19, 24, p. 6294-6934 641 p.

    Research output: Contribution to journalArticle

  3. Trastuzumab and Pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies

    Faratian, D., Zweemer, A. J. M., Nagumo, Y., Sims, A. H., Muir, M., Dodds, M., Mullen, P., Um, I., Kay, C., Hasmann, M., Harrison, D. J. & Langdon, S. P., 1 Jul 2011, In : Clinical Cancer Research. 17, 13, p. 4451-4461 11 p.

    Research output: Contribution to journalArticle

  4. Therapeutic Potential of Replication-Selective Oncolytic Adenoviruses on Cells from Familial and Sporadic Desmoid Tumors

    Peerlinck, I., Amini-Nik, S., Phillips, R. K., Iggo, R., Lemoine, N. R., Tejpar, S. & Vassaux, G., 1 Oct 2008, In : Clinical Cancer Research. 14, p. 6187-6192 6 p.

    Research output: Contribution to journalArticle

ID: 402101

Top