A REVIEW OF THE RELATION OF ACTIVE AND PASSIVE SMOKING TO BREAST CANCER
Alfredo Morabia, M.D., Ph.D. and Martine Bernstein, M.D.
Division of Clinical Epidemiology, University Hospital, Geneva, Switzerland
Abstract
We review the results of studies about smoking and breast cancer. Most studies compared active smokers to non-active smokers. Fewer compared active or passive smokers to women never regularly exposed to tobacco smoke. We also review the possible effect modifications of the smoking-breast cancer connection by estrogen receptor status or by genetic predisposition. We finally discuss the relevance of the smoking-lung cancer model to study the effect of smoking on breast cancer, the possible biological mechanisms of the smoking effect and the likelihood that some of the reviewed results are due to bias. Overall, epidemiological findings are insufficient to claim that the association is causal, but there is no solid counter-argument to attribute these results to bias.
(Journal of Women’s Cancer, Vol. 2 Number 1:1-9, 2000)
GENISTEIN: MAMMARY CANCER CHEMOPREVENTION, IN-VIVO MECHANISMS OF ACTION, POTENTIAL FOR TOXICITY, AND BIOAVAILABILITY IN RATS
Coral A. Lamartiniere, Ph.D. Department of Pharmacology and Toxicology, 1670 University Boulevard, University of Alabama at Birmingham, Birmingham, AL 35294 USA
Abstract
Asian women consuming a traditional diet high in soy have a low incidence of breast cancer. However, when Asians emigrate to the U.S., future generations of Asians lose this protection. We have hypothesized that early exposure to genistein, a major component of soy, could have a permanent protective effect against breast cancer. To test this hypothesis, we have exposed Sprague Dawley CD rats to neonatal and prepubertal injections of pharmacological doses of genistein, and perinatally to physiological doses of genistein in the diet. These treatments resulted in reduced number of dimethylbenz [a] anthracene (DMBA)-induced mammary tumors in the adults. The initial effect of early exposure to genistein was to up-regulate the EGF-signaling pathway and to down-regulate TGF-beta expression. These actions enhanced cell differentiation, resulting in terminal ductal structures and cells that in adulthood are now characterized as having a reduced EGF-signaling pathway. These differentiated cells are less proliferative and less susceptible to carcinogenesis. Bioavailability studies revealed that 25 and 250 mg genistein/kg diet resulted in blood total genistein concentrations of 54 to 1810 pmol/ml in prepubertal rats. These "frame" the 276 pmol total genistein/ml concentration found in Asians eating a traditional diet high in soy, and are lower than blood genistein concentrations in babies fed soy infant formula. Genistein is demonstrated to be bioavailable to the mammary gland in postnatal rats. Prenatal genistein in the diet (250 mg/kg) did not protect against DMBA-induced mammary cancer or result in significant toxicity to the F1 female reproductive tract. Prenatal exposure to genistein via the diet yielded only 43-pmol total genistein/ml blood in the fetus. We conclude that in utero exposure to genistein via the diet did not protect against mammary cancer or cause toxicity because conjugated genistein does not cross the placental barrier. Our results demonstrate that postnatal exposure of rats to physiological concentrations of genistein in the diet is a safe and effective means of programming against chemically induced mammary cancer. (Journal of Women’s Cancer, Vol. 2 Number 1:11-19, 2000)
ESTROGEN, ESTROGEN RECEPTORS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS IN HUMAN BREAST CANCER
Suzanne A.W. Fuqua, Ph.D. 1, Jose Russo, M.D.2, Stanley E, Shackney, M.D.3, and Mark E. Stearns, Ph.D.41 Suzanne A.W. Fuqua, Ph.D., Division of Medical Oncology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.2 To whom correspondence, reprint request and galley proofs must be addressed at: Jose Russo, M.D. Breast Cancer Research Laboratory, Fox Chase Cancer Center,7701 Burholme Avenue, Philadelphia, PA 191 11, Phone: 215 728-4782, FAX: 215 728-2180. 3 Stanley E. Shackney, M.D., Department of Oncology and Human Genetics, Allegheny General Hospital, 320 East North Ave., Pittsburgh, PA 15212. 4 Mark E. Steams, Ph.D., Department of Pathology, Medical College of Pennsylvania and Hahnemann University, Broad & Vine St., Philadelphia, PA 19102.
Abstract Endocrine factors are highly relevant in the pathogenesis of breast cancer. Among these hormonal influences, a leading role is attributed to estrogens, either of ovarian or extra-ovarian origin, as supported by the observations of slightly higher breast cancer incidence in women receiving hormone replacement therapy or in those with postmenopausal obesity. This role is further confirmed by the inhibition of tumor growth by treatment with antiestrogens. Estrogens are essential for the normal development of the breast and uterus, and are also important for the development of both breast and endometrial cancer. The biological responses of those organs to this steroid hormone are mediated by their content of estrogen receptors (ER), which are localized in the nucleus, now known as ER-alpha. The presence of ER-alpha in target tissue or cells is essential to their responsiveness to estrogen action. In fact, the expression levels of ER-alpha in a particular tissue have been used as an index for the degree of estrogen responsiveness. Recently, this paradigm has evolved to include a second type of receptor, ER-beta, which has been cloned from rat, mouse, and human tissues. The existence of two ER subtypes and their ability to form DNA-binding heterodimers suggests multiple potential pathways of estrogen signaling- one via the ER-alpha or ER-beta subtype in tissues exclusively expressing each subtype, or via the formation of heterodimers in tissues expressing both ER-alpha and ER-beta. Estrogens are considered to play a major role in promoting the proliferation of both the normal and the neoplastic breast epithelium. The proliferative activity of the mammary epithelium in both rodents and humans varies with the degree of differentiation of the mammary parenchyma. Historically, studies of the molecular mechanisms underlying estrogen dependence/ independence and selective estrogen receptor modulators (SERM) action have focused on the molecular interactions that affect the ER complex as a transcriptional activator of estrogen-responsive genes. The estrogen receptor protein binds to DNA at specific sites known as estrogen response elements (ERE's), and stimulates the transcription of specific genes through two ER transcriptional activation domains called AF-1 and AF-2. ER-mediated transcriptional activation is thought to be modulated by the molecular conformational changes induced by the binding of estrogens or antiestrogens. Such conformational changes can differentially modify the transcriptional effects mediated by the AF-1 and AF-2 domains. ER-induced transcriptional activation is also affected by the presence or absence of a variety of co-activator and co-repressor proteins, expression patterns of which may be cell type-specific. But a further complication to a simple receptor: co-activator/co-repressor model is the finding that there is actually a specificity to the ligand: receptor complex for individual DNA response elements which then may control their eventual response in cells. This suggests that there may be gene-specific ligands which could be developed and exploited clinically to the receptor: ligand: DNA complex to effect receptor action. Even though the interplay among these different effects and the relative importance of their contributions to estrogen-dependent cell proliferation and cell differentiation remain to be determined, the clinical utilization of specific modulators of estrogen receptors has been a major breakthrough in translational cancer research. An overview of these possibilities is the subject of this work.
(Journal of Women’s Cancer, Vol. 2 Number 1:21-32, 2000)
ErbB2 OVEREXPRESSION IN BREAST CANCER: BIOLOGY AND CLINICAL TRANSLATION
Chris Benz, M.D. and Debu Tripathy, M.D. Division of Oncology-Hematology
Department of Medicine, University of California, San Francisco
Abstract
Overexpression of ErbB2 (HER2/neu) occurs early during the breast tumorigenic process and results from transcriptional upregulation of the genomically amplified c-erbB2 oncogene. As a prognostic marker, ErbB2 overexpression is found in 25-30% of invasive ductal breast cancers in which it is associated with more aggressive clinical behavior characterized by early metastatic tumor spread and reduced patient survival. More important than its prognostic utility, ErbB2 positivity is now a predictive marker since the overexpressed p185 kDa membrane receptor tyrosine kinase is both tumor target for a newly approved therapeutic antibody (Herceptin/trastuzumab) and associated with altered clinical responsiveness to standard breast cancer therapeutics. Despite 15 years of research focused on this oncogenic receptor system, however, we still lack full understanding about its tumorigenic mechanism(s) and explanation for the heterogeneous clinical behavior of ErbB2 overexpressing breast tumors including the failure of many to be growth suppressed by Herceptin.
(Journal of Women’s Cancer, Vol. 2 Number 1:33-40, 2000)
INSULIN-LIKE GROWTH FACTORS IN BREAST CANCER
Farideh Garmroudi, Ph.D. and Kevin J. Cullen, MD . Lombardi Cancer Center, Georgetown University, Washington DC USA
Abstract
The Insulin-like growth factor (IGF) family of ligands, receptors, and binding proteins regulate cellular activities involving cell proliferation, differentiation, and apoptosis. Current evidence suggests that the IGF family modulates mammary gland cell proliferation both in vivo and in vitro and that deregulation of these pathways are key elements to the development of breast cancer. The mitogenic action of IGFs is mediated through IGF-I receptor (IGF-IR) signaling which is involved in anti-apoptotic activity and cell survival in breast malignancy. Other members of the IGF family may serve to regulate IGF-IR signaling. Thus, measurement of IGF expression and function may provide new diagnostic tools and targets for treatment of the disease. Association of the IGF family with steroid hormones, growth factors and other molecules adds to the complexity of this system, but these interactions are being exploited for new approaches to cancer prevention. While involvement of IGFs in many types of cancers is an active area of study, the focus of this article is to review IGF involvement in the development and progression of breast cancer. (Journal of Women’s Cancer, Vol. 2 Number 1:41-52, 2000)
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