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-B-hydroxysteroid dehydrogenase, an enzyme that mainly degrades active 17-B-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. (Cancer Res 2006; 66(1): 29-33)

Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes

“…Previous studies have reported the association of DNA methylation patterns with molecular subtypes of breast cancer through hormone receptor and HER2/neu status. [14][15][16][17]35 In an early study by Sunami et al, 14 double-negative (ER-negative, HER2/neunegative) breast cancers, corresponding to the basal-like subtype, were reported to have lower frequencies of RASSF1A, GSTP1, and APC methylation, and this was confirmed in the present study. Suijkerbuijk et al 36 examined the methylation of 11 genes involved in breast carcinogenesis (RARB, RASSF1, TWIST, CCND2, ESR1, SCGB3A1, BRCA1, BRCA2, CDKN2A, APC, CDH1) by quantitative multiplex methylation-specific PCR in BRAC1-associated and sporadic breast cancers, and showed that the median values for RASSF1, TWIST, SCGB3A1, APC, and the cumulative methylation index for the 11 genes, were significantly lower in BRAC1-associated hereditary breast cancers than in sporadic ones.…”

“…7 There are reports that promoter CpG island hypermethylation is associated with various histopathologic characteristics of breast cancers, including histologic type, 10,11 tumor grade, 12,13 hormone receptor, and HER2/neu status. [14][15][16][17] Array-based comprehensive DNA methylation profiling has shown that breast cancer molecular subtypes have their own methylation profiles. [18][19][20][21] Moreover, these different methylation profiles were evident throughout the CpG islands of the genome, not limited to functional genes.…”

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

“…Our data show that although somatic alterations can occur in CAFs, they are exceedingly rare and are unlikely to be responsible for the stable cancer-promoting attributes of CAFs. However, our findings cannot exclude the possibility that other mechanisms, such as epigenetic changes, have a role in the tumor-promoting phenotype of CAFs 18,25 .…”

Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice

“…Some authors think that MTCs come directly from cancer cells as a consequence of epithelialmesenchymal transition (Petersen et al, 2001;Pennacchietti et al, 2003;Knutson et al, 2006;Thiery and Sleeman, 2006). An alternative explanation is that MTCs derive from preexisting stromal fibroblasts or their precursors, following microenvironmentally induced 'epigenetic changes' (Kurose et al, 2002;Hu et al, 2005;Fiegl et al, 2006).…”