Further contributing to this variation is the fact that the presence of ER is necessary for ER pathway activity, but not always sufficient, as reported for breast cancer.12,33 With the exception of rare ER-activating mutations, locally present oestradiol is required to activate the ER, and availability of such factors depends on menopausal status and local oestrogen production (e.g., from fat cells or local aromatase). This evidence concerns the gene CYP19A1 and breast carcinoma.