Abstract

Biological markers associated with in situ carcinoma and atypical intraductal hyperplasia in the breast are examined to help in identifying a subgroup of premalignant lesions whose natural history may be influenced by epigenetic factors. The biomarkers may be used as indices in clinical trials aiming to assess the effect of weight reduction, dietary intervention or hormone replacement therapy on the risk of progression to invasive breast cancer. In the current state of knowledge, the expression of oestrogen receptors, p53, bcl-2 and HER-2 neu oncogenes and the Ki-67 index of proliferative activity, are the most useful biomarkers for this purpose. In situ carcinoma of the breast manifests a variety of morphological phenotypes with specific biological characteristics. There is evidence that only a proportion of premalignant lesions are committed to progression to invasive cancer while other lesions undergo spontaneous regression at the time of the menopause. Cross-cultural studies suggest that it is the late-stage epigenetic promoting factors which are responsible for the high incidence of postmenopausal breast cancer in Western women. Obesity in middle life and the Western diet favour the development of hyperinsulinaemic insulin resistance, and the metabolic-endocrine effects of its concomitants may promote mammary carcinogenesis around the time of the menopause and increase the incidence of invasive cancer after the menopause. Because biomarker changes in premalignant lesions are nearer in time to these promoting influences, they could provide intermediate endpoints for testing the hypothesis.