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Hormonally induced differentiation: A novel approach to breast cancer prevention

Breast cancer, one of the most common neoplasms in women, develops more frequently in those who are nulliparous or late parous, who experience early menarche and late menopause and have a family history of breast cancer. Early parity, late menarche, early menopause, and hormone deprivation exert a protective effect. The mechanisms modulating these variations in malignancy susceptibility are not known. Epidemiologic and experimental studies indicate that malignancies develop in the mammary gland as a result of exposure to carcinogenic stimuli (i.e., chemical carcinogens, radiation). Neo‐plastic transformation requires that the gland be under specific developmental and age‐related conditions at the time of exposure to such agents. In the rat, maximal susceptibility to neoplastic transformation is exhibited by the highly proliferating and undifferentiated gland of the young, virgin, intact females, whereas the fully differentiated gland of parous rats and virgin rats treated with the placental hormone human chorionic gonadotropin is protected from tumor development. Hormonally induced differentiation of the mammary gland is a novel approach to breast cancer prevention and therapy. The development of clinical protocols capitalizing on the protective effect of hormonal treatments mimicking pregnancy in humans is required to validate observations in experimental animal models, and to determine how they relate to epidemiologic and clinical findings. The feasibility of this approach is supported by the observed parallelism between humans and experimental models in both the site of cancer origin and the changes in breast development occurring with parity. Breast cancer initiates in terminal ductal lobular units or lobules type 1, the most undifferentiated structures frequently found in the breast of young nulliparous women. Lobules type 1 differentiate into lobules type 2, and these into type 3, which progressively develop more alveoli. With pregnancy, these enlarge and rapidly progress to secretory lobules type 4. Even after post‐lactational involution, the breast remains more differentiated. Mammary epithelial cells retain in vitro growth characteristics reflective of the degree of differentiation of the lobule from which they were derived. The identification of morphological in vivo and in vitro proliferative cell characteristics, response to hormones, and expression of gene products of differentiation are useful intermediate endpoints for assessing the potential of the breast for neoplastic transformation and its response to hormonal treatments leading to breast cancer prevention and therapy through induction of differentiation.