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Russo J , Russo IH
Toward a Physiological Approach to Breast-Cancer Prevention
Cancer Epidemiology Biomarkers & Prevention. 1994 Jun;3(4) :353-364
PMID: ISI:A1994NR18900012   
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Breast cancer is one of the most frequent malignancies in women, and its incidence is increasing. No reduction in the mortality rate has resulted from advances in early diagnosis and new therapeutic modalities; therefore, new approaches to the understanding of this disease are required. The observation that, in an experimental animal model, full-term pregnancy prior to exposure to a carcinogenic agent protects the mammary gland from malignant transformation led us to study the mechanisms underlying this phenomenon. The protective effect observed after pregnancy did not depend upon gestational or lactational hyperplasia of the mammary gland, but upon structural changes induced in the mammary parenchyma by those processes. Those changes are permanent, since the protective effect is maintained after pregnancy and consists in the complete differentiation of terminal end buds to lobules. The protective effect exerted by pregnancy can be mimicked by treating young virgin rats with a single placental hormone, chorionic gonadotropin. Since the possibility of preventing breast cancer by treating young nulliparous females with hormones that mimic a full-term pregnancy that results in complete differentiation of the gland is of practical interest to the human female population, we undertook the study of the human breast. The breast of postpubertal nulliparous women is composed of lobular structures reflecting different stages of development. Lobules type 1 (lob 1) are the most undifferentiated ones. Lobules type 2 evolve from the previous ones and have a more complex morphology, being composed of a higher number of ductular structures per lobule. They progress to lobules type 3 and 4, which are present in the pregnant and lactational periods of the mammary gland. In nulliparous women the structure most frequently found at all ages is the lob 1, whereas in parous women, lob 3 is the most frequent one. Lob 1 are considered to be the site of origin of ductal carcinoma in situ, which progresses to invasive carcinoma. Lob 2 originate lobular carcinoma and lob 3 originate adenomas, fibroadenomas, sclerosing adenosis, and apocrine cysts. These observations led us to test if the degree of lobular development influences the transformation of human breast epithelial cells exposed in vitro to chemical carcinogens. We found that primary cultures derived from breast tissues composed of lobules type 1 and 2 express phenotypes of cell transformation which were not observed in cells derived from lobules type 3. These data acquire relevance to the light that women with a history of early pregnancy are at a lower risk of developing breast cancer than nulliparous women, an effect attributed to differences in the degree of differentiation of the breast. Therefore, the stimulus of pregnancy furthers the differentiation of lobules type 1 to lobules type 3 and 4. It is postulated that their more differentiated condition makes them refractory to neoplastic transformation. Overall, the data provide a solid basis for developing physiological means of breast cancer prevention and control.