Estrogen Receptor/Progesterone Receptor-Negative Breast Cancers of Young African-American Women Have a Higher Frequency of Methylation of Multiple Genes than Those of Caucasian Women1

Abstract

Purpose: To provide a molecular rationale for negative prognostic factors more prevalent in African-American (AA) than Caucasian (Cau) women, we investigated the frequency of promoter hypermethylation in invasive ductal breast cancers in the two races.Experimental Design: HIN-1, Twist, Cyclin D2, RAR-␤, and RASSF1A were analyzed in DNA from 67 AA and 44 Cau invasive ductal breast cancers, stratified by age and estrogen receptor/progesterone receptor (ER/PR) status, by methylation-specific PCR. Hierarchical multiple logistic regression analysis was applied to determine estimated probabilities of methylation. Expression of HIN-1 mRNA was analyzed by in situ hybridization and quantitative reverse transcribed PCR.Results: Significant differences between races were observed in the ER؊/PR؊, age < 50 subgroup; AA tumors had higher frequency of methylation (P < 0.001) in four of five genes as compared with Cau and also a higher prevalence (80 versus 0%; P < 0.005) of three or more methylated genes per tumor. No differences in gene methylation patterns were observed across the two races for ER؉/PR؉ tumors in all ages and ER؊/PR؊ tumors in age > 50. ER؉/PR؉ status was associated with higher frequency of methylation in Cau tumors of all ages but only with the age > 50 subgroup in AA. Frequent Cyclin D2 methylation was significantly associated (P ‫؍‬ 0.01) with shorter survival time.Conclusion: ER؊/PR؊, age < 50 tumors in AA women, have a significantly higher frequency of hypermethylation than in those of Cau women. Comparative studies, such as these, could provide a molecular basis for differences in tumor progression and pathology seen in the two races.

Breast Cancer Epidemiology in Blacks and Whites: Disparities in Incidence, Mortality, Survival Rates and Histology

“…These differences include a higher prevalence of among black women of breast cancer with poor prognostic indicators such as, no estrogen receptor (ER−) expression 8,9,15,29,34 ; poorly differentiated tumors 8 ; basal-like tumor substype 35 ; high nuclear grade 34,36,37 and high S-phase 36 ; higher frequency of hypermethylation in ER−/PR− and being younger (<50 years) with breast cancer 38 ; higher mitotic index and marked tumor necrosis 34,37 ; defects in specific cell cycle-regulatory proteints 34 ; overexpression of p53 39 ; and tumors that are grade-III, and high grade nuclear atypia 37 . Premenopausal black women, unlike postmenopausal black and non-black women, have a higher prevalence of basal-like subtype of breast tumors 35 .…”

Detection of RASSF1A and RAR? Hypermethylation in Serum DNA from Breast Cancer Patients

“…RASSF1A has been reported to be frequently hypermethylated in breast cancer. 16,18,19 Furthermore, the potential of RASSF1A promoter methylation in circulating DNA has been explored as a marker for monitoring the efficacy of adjuvant therapy and predicting disease outcome in breast cancer patients. 42 In view of the clinical utility of RASSF1A as a marker we chose to determine its methylation status in breast tumors and paired sera.…”

“…Loss of expression of RARβ, a potent tumor suppressor gene, primarily mediated by promoter methylation induced gene silencing has been reported in breast carcinomas. 16,51,52,58,60 High frequency of RARβ methylation has been observed in breast cancer metastasis to the bone, brain and lung. Most often it is not the primary tumor, but metastasis to distant organs that results in the death of breast cancer patients.…”

“…Most often it is not the primary tumor, but metastasis to distant organs that results in the death of breast cancer patients. 16,57 In this context hypermethylation mediated RARβ gene silencing and consequent reduction or loss in RARβ protein expression may serve as an important biomarker to predict risk of metastasis in breast cancer. Moreover, endogenous reactivation of RARβ has been demonstrated by inducing histone reacetylation at RARβ P2 promoter in breast xenograft tumors and breast cancer cell lines, suggesting that RARβ is an important target for therapy.…”

“…[10][11][12][13][14] Recent studies suggest that methylation profiles of cancers are tumor type and ethnicity specific. [15][16][17] There are several reports on methylation profiles of breast cancer patients from Western population. [18][19][20][21] However, to our knowledge there is no study in the Indian population till date.…”