title: Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer.
abstract: The HER-2/neu gene is amplified and overexpressed in 20% to 30% of invasive breast carcinomas and is associated with increased metastatic potential and less tamoxifen sensitivity. We generated the DNA methylation profiles of 143 human breast tumors and found significant differences in HER-2/neu expression and DNA methylation of five genes. For three of these five genes [PGR (coding for the progesterone receptor), HSD17B4 (coding for type 4 17-beta-hydroxysteroid dehydrogenase, an enzyme that mainly degrades active 17-beta-estradiol into inactive metabolites), and CDH13 (coding for H-cadherin)] a higher prevalence of DNA methylation in HER-2/neu-positive cancers was confirmed in an independent set of microdissected primary breast cancers. DNA methylation was not only present in cancer cells but also in the tumor stroma fraction. Of the isolated fractions in HER-2/neu-positive versus -negative cancers, 27.1% versus 10.5%, respectively, showed DNA methylation of the five genes (P = 0.011, Fisher's exact test). In Her-2++/+++ breast cancers, HSD17B4 mRNA expression was inversely associated with HSD17B4 methylation (P = 0.04). These data support the view that in addition to HER-2/neu-associated signaling, epigenetic changes in cancer as well as in tumor stroma cells might attribute to the specific biological features of HER-2/neu-positive cancers.
authors.affiliation: Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.forename: Simone
authors.initials: S
authors.lastname: Millinger
authors.forename: Georg
authors.initials: G
authors.lastname: Goebel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Müller-Holzner
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D015067:17-Hydroxysteroid Dehydrogenases; D018931:Antineoplastic Agents, Hormonal; D015820:Cadherins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D013629:Tamoxifen; C099972:H-cadherin