Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF

Gregory R. Bean, Andrew D. Bryson, Patrick G. Pilie, Vanessa Goldenberg, Joseph C. Baker, Catherine Ibarra, Danielle M.U. Brander, Carolyn Paisie, Natalie R. Case, Mona Gauthier, Paul A. Reynolds, Eric Dietze, Julie Ostrander, Victoria Scott, Lee G. Wilke, Lisa Yee, Bruce F. Kimler, Carol J. Fabian, Carola M. Zalles, Gloria BroadwaterThea D. Tlsty, Victoria L. Seewaldt

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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 hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation 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-β2, estrogen receptor-α, and breast cancer-associated 1 genes (P = 0.001). Conclusions: Because INK4a/ARF promoter hypermethylation 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.

Original languageEnglish (US)
Pages (from-to)6834-6841
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number22
DOIs
StatePublished - Nov 15 2007

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Methylation
Breast
Epithelial Cells
DNA Methylation
Breast Neoplasms
Cell Biology
Retinoic Acid Receptors
Chromatin Assembly and Disassembly
Cell Aging
Fine Needle Biopsy
Estrogen Receptors
Neoplasms
Cell Cycle
Research Design
Phenotype
Genes

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Bean, G. R., Bryson, A. D., Pilie, P. G., Goldenberg, V., Baker, J. C., Ibarra, C., ... Seewaldt, V. L. (2007). Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF. Clinical Cancer Research, 13(22), 6834-6841. https://doi.org/10.1158/1078-0432.CCR-07-0407

Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF. / Bean, Gregory R.; Bryson, Andrew D.; Pilie, Patrick G.; Goldenberg, Vanessa; Baker, Joseph C.; Ibarra, Catherine; Brander, Danielle M.U.; Paisie, Carolyn; Case, Natalie R.; Gauthier, Mona; Reynolds, Paul A.; Dietze, Eric; Ostrander, Julie; Scott, Victoria; Wilke, Lee G.; Yee, Lisa; Kimler, Bruce F.; Fabian, Carol J.; Zalles, Carola M.; Broadwater, Gloria; Tlsty, Thea D.; Seewaldt, Victoria L.

In: Clinical Cancer Research, Vol. 13, No. 22, 15.11.2007, p. 6834-6841.

Research output: Contribution to journalArticle

Bean, GR, Bryson, AD, Pilie, PG, Goldenberg, V, Baker, JC, Ibarra, C, Brander, DMU, Paisie, C, Case, NR, Gauthier, M, Reynolds, PA, Dietze, E, Ostrander, J, Scott, V, Wilke, LG, Yee, L, Kimler, BF, Fabian, CJ, Zalles, CM, Broadwater, G, Tlsty, TD & Seewaldt, VL 2007, 'Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF', Clinical Cancer Research, vol. 13, no. 22, pp. 6834-6841. https://doi.org/10.1158/1078-0432.CCR-07-0407
Bean, Gregory R. ; Bryson, Andrew D. ; Pilie, Patrick G. ; Goldenberg, Vanessa ; Baker, Joseph C. ; Ibarra, Catherine ; Brander, Danielle M.U. ; Paisie, Carolyn ; Case, Natalie R. ; Gauthier, Mona ; Reynolds, Paul A. ; Dietze, Eric ; Ostrander, Julie ; Scott, Victoria ; Wilke, Lee G. ; Yee, Lisa ; Kimler, Bruce F. ; Fabian, Carol J. ; Zalles, Carola M. ; Broadwater, Gloria ; Tlsty, Thea D. ; Seewaldt, Victoria L. / Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 22. pp. 6834-6841.
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title = "Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF",
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 hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation 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-β2, estrogen receptor-α, and breast cancer-associated 1 genes (P = 0.001). Conclusions: Because INK4a/ARF promoter hypermethylation 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.",
author = "Bean, {Gregory R.} and Bryson, {Andrew D.} and Pilie, {Patrick G.} and Vanessa Goldenberg and Baker, {Joseph C.} and Catherine Ibarra and Brander, {Danielle M.U.} and Carolyn Paisie and Case, {Natalie R.} and Mona Gauthier and Reynolds, {Paul A.} and Eric Dietze and Julie Ostrander and Victoria Scott and Wilke, {Lee G.} and Lisa Yee and Kimler, {Bruce F.} and Fabian, {Carol J.} and Zalles, {Carola M.} and Gloria Broadwater and Tlsty, {Thea D.} and Seewaldt, {Victoria L.}",
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T1 - Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF

AU - Bean, Gregory R.

AU - Bryson, Andrew D.

AU - Pilie, Patrick G.

AU - Goldenberg, Vanessa

AU - Baker, Joseph C.

AU - Ibarra, Catherine

AU - Brander, Danielle M.U.

AU - Paisie, Carolyn

AU - Case, Natalie R.

AU - Gauthier, Mona

AU - Reynolds, Paul A.

AU - Dietze, Eric

AU - Ostrander, Julie

AU - Scott, Victoria

AU - Wilke, Lee G.

AU - Yee, Lisa

AU - Kimler, Bruce F.

AU - Fabian, Carol J.

AU - Zalles, Carola M.

AU - Broadwater, Gloria

AU - Tlsty, Thea D.

AU - Seewaldt, Victoria L.

PY - 2007/11/15

Y1 - 2007/11/15

N2 - 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 hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation 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-β2, estrogen receptor-α, and breast cancer-associated 1 genes (P = 0.001). Conclusions: Because INK4a/ARF promoter hypermethylation 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.

AB - 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 hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation 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-β2, estrogen receptor-α, and breast cancer-associated 1 genes (P = 0.001). Conclusions: Because INK4a/ARF promoter hypermethylation 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.

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