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Cancers 2011, 3(2), 1580-1592; doi:10.3390/cancers3021580
Article

Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer

1
,
1
,
2
 and
1,*
1 Department of Otolaryngology/Head and Neck Surgery, Henry Ford Hospital, 1 Ford Place, 1D, Detroit, MI 48202, USA 2 Department of Pathology, Henry Ford Hospital, Detroit, 1 Ford Place, 1D, Detroit, MI 48202, USA
* Author to whom correspondence should be addressed.
Received: 13 January 2011 / Revised: 10 March 2011 / Accepted: 22 March 2011 / Published: 29 March 2011
(This article belongs to the Special Issue Epigenetics of Cancer Progression)
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Abstract

Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies the pathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.
Keywords: benign; premalignant; transformation; DNA methylation; progression; continuum benign; premalignant; transformation; DNA methylation; progression; continuum
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Chen, K.M.; Stephen, J.K.; Raju, U.; Worsham, M.J. Delineating an Epigenetic Continuum for Initiation, Transformation and Progression to Breast Cancer. Cancers 2011, 3, 1580-1592.

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