Retinoic Acid Receptor-β2 Promoter Methylation in Random Periareolar Fine Needle Aspiration

Abstract

Methylation of the retinoic acid receptor-B2 (RARB2) P2 promoter is hypothesized to be an important mechanism for loss of RARB2 function during early mammary carcinogenesis. The frequency of RARB2 P2 methylation was tested in (a) 16 early stage breast cancers and (b) 67 random periareolar fine needle aspiration (RPFNA) samples obtained from 38 asymptomatic women who were at increased risk for breast cancer. Risk was defined as either (a) 5-year Gail risk calculation z z1.7%; (b) prior biopsy exhibiting atypical hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ; or (c) known BRCA1/2 mutation carrier. RARB2 P2 promoter methylation was assessed at two regions, M3 (À À51 to 162 bp) and M4 (104-251 bp). In early stage cancers, M4 methylation was observed in 11 of 16 (69%) cases; in RPFNA samples, methylation was present at M3 and M4 in 28 of 56 (50%) and 19 of 56 (38%) cases, respectively. RPFNAs were stratified for cytologic atypia using the Masood cytology index. The distribution of RARB2 P2 promoter methylation was reported as a function of increased cytologic abnormality. Methylation at both M3 and M4 was observed in (a) 0 of 10 (0%)

Hypermethylation of theBreast Cancer–Associated Gene 1Promoter Does Not Predict Cytologic Atypia or Correlate with Surrogate End Points of Breast Cancer Risk

“…The presence of detectable cellular atypia in a breast RPFNA specimen has been prospectively validated to confer a 5.6-fold increase in breast cancer risk in high-risk women (26). These studies underscore the use of RPFNA as a translational research tool, and as in our previous work, RPFNA can be used to couple cytologic analysis and methylation studies (28).…”

“…As indicated in previous studies, RPFNA has the advantage of being able to provide a ''snapshot'' of the whole breast, can be done successfully in a majority of high-risk women (72-85% cell yield), and has been validated in long-term chemoprevention cohorts (26)(27)(28). In high-risk women, the acceptance rate of RPFNA is high and f80% of women who undergo initial RPFNA return for subsequent RPFNA (26,27).…”

Overweight and Obese Perimenopausal and Postmenopausal Women Exhibit Increased Abnormal Mammary Epithelial Cytology

“…RPFNA was done as previously published (11). In subjects with prior invasive cancer or ductal carcinoma in situ, only the contralateral breast was aspirated.…”

Breast-tissue sampling for risk assessment and prevention

“…RASSFIA is involved with the regulation of cell-cycle progression via inhibition of cyclin D1 accumulation and promotion of apoptosis. Low-frequency promoter methylation of GSTP, CDH, BRCA1, p16 and RARb2 have all been observed in benign breast tissue (Troch et al 2003, Bae et al 2004, Bean et al 2005. These abnormalities allow escape from normal senescence and apoptosis and an extended period of susceptibility to proliferation and carcinogenic influences (Widschwendter et al 1997, Huschtscha et al 1998, Nuovo et al 1999, Tlsty et al 2001, Neumeister et al 2002, Holst et al 2003.…”