Epigenetic marks in estrogen receptor alpha CpG island correlate with some reproductive risk factors in breast cancer.

Reproductive backgrounds, such as age at menarche and menopause, age of first full-term pregnancy (FFTP), number of full-term deliveries and oral contraceptive use are main hormone-related risk factors of breast cancer. It seems that the mentioned factors may affect the risk of breast cancer by enhancing the duration of exposure to estrogen as a potent carcinogen for breast tissue, but the molecular mechanism which links each risk factor to breast cancer is unclear. Estrogen mainly works via its nuclear receptor (ERα). As epigenetic alterations such as CpG methylation are potential links between endogenous or exogenous exposures and genome, we hypothesized that hormone-related risk factors may correlate with the epigenetic marks of the ERα promoter in breast tumors. In the present study, the CpG methylation status of the ERα gene in 99 samples of breast tumors belonged to women with different reproductive histories was evaluated. The reproductive history data were collected from patients. ERα CpG methylation was investigated by methylation specific PCR in DNA samples were obtained from the breast tumors. We could show that some of the hormone-related risk factors (early FFTP and increased number of pregnancies) were inversely correlated with epigenetic marks in ERα gene in breast tumors. Other hormone-related risk factors such as age of menarche and menopause and oral contraceptive use did not show any association with ERα methylation. It seems that pregnancy-related risk factors in comparison with other hormone-related factors work via different mechanism. As ERα methylation is a poor prognosis marker in breast tumors, its association with some modifiable reproductive risk factors (FFTP age and numbers of pregnancies) reiterates the importance of programming reproductive life style not only for prevention of breast cancer but also in favoring the prognosis of the affected women. The exact molecular mechanisms of the observed correlation need more investigation in the future.