Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis.

Abstract

An attempt has been made to put forward a unifying hypothesis explaining the role hormones play in the genesis of mammary cancers of different phenotypes and genotypes in mice, rats, and humans. Most mammary cancers in these species originate in luminal mammary epithelial cells lining the mammary ducts and alveoli. These cancers are histopathologically diverse and are classified on the basis of growth requirements as hormone-dependent or hormone-independent tumors. In most strains of mice, mammary cancers at the time of detection are largely of the hormone-independent type; in rats, almost all mammary cancers are hormone-dependent, while humans have both phenotypes. In spite of these differences, in vivo studies show that hormones (ovarian and pituitary) are essential for luminal mammary epithelial cell proliferation and also for the development of mammary cancers of both hormone-independent and hormone-dependent types. This article, based on our extensive in vivo and in vitro studies and on current literature, proposes a model to explain the central role of hormones in the genesis of all types of mammary cancers. The model attempts to address the following questions: (i) how hormones regulate luminal mammary epithelial cell proliferation, (ii) why hormones are required for the genesis of mammary cancers of all phenotypes and genotypes, including those which are always classified as hormone-independent tumors, and (iii) why the three species (mouse, rat, and human) have consistently different ratios of hormone-dependent to hormoneindependent tumors.Breast cancer is the most common cancer in American women and is second only to lung cancer as a cause of cancer deaths. Despite advances in the early detection and treatment of breast cancer, the morThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. tality rate from breast cancer has not changed appreciably in the last few decades. Unfortunately, in contrast to the known increased risk for lung cancer associated with cigarette smoking, no single major etiological agent is known for breast cancer. Epidemiological studies have identified various risk factors, including hormone-related factors, but taken together, these risk factors seem to account for only a third of breast cancer cases (1, 2). A search for appropriate preventive measures will require a thorough understanding of the etiology of this disease and of the mechanisms involved in the genesis of breast cancers of different phenotypes and genotypes.Animal and human studies indicate that an appropriate hormonal milieu is required for proliferation of mammary epithelial cells and is also prerequisite for breast carcinogenesis. This article, based on our extensive in vivo and in vitro studies and on an analysis of the literature, will put forward a unifying hypothesis that offers an explanation of the role that hormones may play in the genesis of ma...

In utero alcohol exposure increases mammary tumorigenesis in rats

“…Oestrogens stimulate normal mammary epithelial and tumour cell proliferation (Nandi et al, 1995), also when administered neonatally (Hilakivi-Clarke et al, 1997a, b). In vitro and in vivo studies show that alcohol increases normal and malignant mammary cell In utero alcohol exposure and breast cancer risk L Hilakivi-Clarke et al proliferation .…”

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

“…Together with the fact that only a small percentage of mammary epithelial cells express ERa (Petersen et al, 1987;Ricketts et al, 1991), it has been suggested that breast cancer may initiate from ER-positive cells but become ER-negative and estrogen-independent in its growth at later stages (Moolgavkar et al, 1980). The observation that mammary tumors arise in both ERKO and ovariectomized mice supports an alternative model that a fraction of breast cancers may directly evolve from ERa-negative cells (Nandi et al, 1995), an idea that needs to be tested with other oncogenic transgenes.…”

Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

“…Prolonged exposure to estrogens is a major etiologic factor in the causation of estrogenmediated cancers (116,117). Two prevailing hypotheses regarding the etiology of estrogen-mediated cancers prevail in the literature.…”