Critical Steps in Breast Carcinogenesis^a

Abstract

Based upon our previous observations that the susceptibility of the mammary gland to neoplastic transformation is related to its degree of development and proliferative activity,8-10 we studied 15 reduction mammoplasties by determining the degree of breast development, measured based upon the type and number of lobules present," which allowed us to classify the mammoplasty specimens into two types: (a) poorly differentiated breasts, those composed oftype 1 and 2 lobules; and (b) well-differentiated breasts, those composed almost exclusively of type 3 lobules.1° Portions of the same breasts were utilized for measuring the rate of DNA synthesis or DNA labeling index (DNA-LI) by in vim incorporation of 3H-thymidine and for studying the in vim growth characteristics of organoids obtained by digestion of the tissue prior to plating. It was found that 10 of the breasts were composed predominantly of type 1 and 2 lobules, and their DNA-LI was 1.03 f 0.48. Cells derived from these samples attached to the culture dish immediately, with a high number of doublings (0.64 f 0.47). Five samples were composed almost exclusively of type 3 lobules. Their DNA-LI was 0.05 f 0.05, markedly lower than the DNA-LI of cells derived fiom poorly differentiated breasts; the dfferences were statistically significant (FIG. 1). The cells' number of doublings was 0.11 f 0.06. There was a high correlation coefficient (r = 0.802) between the number of doublings of cells in primary cultures and the percentage of type 1 and 2 lobules present in the specimen, whereas differentiation inversely correlated with this parameter (r = 0.722) (FIGS. 2 and 3). 1.6 1 --If DNA-LI FIGURE 1. Influence of lobulardevelopment on the number of doublingdday and DNAlabeling index. RUSSO ct uf.: CRITICAL STEPS 1 -0 -3 Y=0.0*2 -0 . 2 6 0~ @ \ @ I 1 0 Y=O. 126+0.35Bx Corr. =O .802 FIGURE 2. Correlation of doublingdday and type 1 and type 2 lobular structures. RESPONSE OF HUMAN BREAST EPITHELIAL CELLS IN PRIMARY CULTURES To CARCINOGEN TREATMENTTwenty additional reduction mammoplasty specimens were digested for obtention of organoids, which were classified as type 1, 2, or 3 lobules. The organoids were plated in DMEM:F12 culture medium containing 1.05 mM calcium (Ca++). When they formed monolayers, the cells were passaged and then treated with the following carcinogens: 7,12-dimethylbenz(a)anthracene (DMBA), N-methyl-N-nitrosourea (NMU), methyl-N-nitro-nitrosoguanidine

Clinicopathological Significance of Reduced SPARCL1 Expression in Human Breast Cancer

“…It can be deemed as a result of cell growth regulation abnormality caused by the inactivation of tumor suppressors and activation of oncogenes (Russo et al, 1993). In recent years, a multitude of relevant molecules have been demonstrated to be implicated in the development and progression of breast cancer, making it possible to propose novel strategies for cancer diagnosis and treatment (Rosman et al, 2007).…”

Increased cancer burden among pesticide applicators and others due to pesticide exposure

“…172,173 During mammary gland development, breast epithelium may be particularly susceptible to environmental carcinogens. 174,175 For instance, exposure to ionizing radiation at an early age confers an increased risk of developing breast cancer as compared with exposure that occurs at later ages. 176,177 Regarding early-life exposure to OC insecticides and breast cancer risk, Cohn et al 168 conducted a nested case-control study among a cohort of female members of the Kaiser Permanente Health Plan in Oakland, California and used stored blood samples that were collected between 1959 and 1967 to assay for serum p,p'-DDT.…”

Estradiol Metabolism: An Endocrine Biomarker for Modulation of Human Mammary Carcinogenesis

“…The mitogenic stimulus mediated via E2 may predispose nontransformed cells for initiation of carcinogenesis, while in preinitiated cells, this stimulus may promote the expression of the transformed cell phenotype (2,3,(5)(6)(7)(8)(10)(11)(12).…”

“…In these studies alteration in E2 metabolism was detected by specific and significant increase in C16a-hydroxylation, with a concomitant decrease in C2-hydroxylation pathways, while aberrant hyperproliferation was quantified by the relative extent of cell proliferation in anchoragedependent and anchorage-independent conditions of growth. Altered cellular metabolism of E2 and aberrant hyperproliferation, therefore, represent biochemical and cellular surrogate end point biomarkers for mammary carcinogenesis (4,9,(17)(18)(19)(20)(21) (2,4,(17)(18)(19). The tissue culture technology and biomarker assays established for the murine models have been optimized for human mammary tissue (4,22,23).…”

“…represent promotion and progression of the preneoplastic phenotype to tumorigenic phenotype with metastatic potential (2,3). Identification and validation of biomarkers for preneoplastic transformation, therefore, may provide important leads not only for identifying markers of risk for developing breast cancer but also for evaluating effective primary or secondary prevention (4)(5)(6)(7)(8)(9).…”