Human Breast Carcinogenesis Research Articles

MMTV-induced mutations in mouse mammary tumors: their potential relevance to human breast cancer.

In mouse mammary tumor virus (MMTV) infected mice, three identifiable stages of mammary tumorigenesis can be biologically defined: preneoplastic hyperplastic nodules, malignant tumor, and distant metastatic lesions (primarily in the lung). MMTV is a biological carcinogen which induces somatic mutations as consequence of its integration into the host cellular genome. Each stage of mammary tumorigenesis appears to result from the clonal outgrowth of cells containing additional integrated proviral MMTV genomes. This phenomenon has provided the basis for an approach to identify genes which, when affected, may contribute to progression through the different stages of mammary tumorigenesis. Eight different genes (Wnt1, Wnt3, Wnt10b, Fgf3, Fgf4, Fgf8, Int3, and Int6) have been shown to be genetically altered in multiple mammary tumors as a consequence of MMTV integration. Although the significance of the human homologs of these genes as targets for somatic mutation during human breast carcinogenesis is only now being explored, it is clear that this work has led to a new appreciation of the complexity of the genetic circuitry that is involved in the control of normal mammary gland growth and development. It seems likely that some of the mutations induced by MMTV, and the signaling pathways in which these target genes take part, will be relevant to the progression from preneoplastic lesions to distant metastasis in human breast cancer.

Carotenoids induce morphological changes in human mammary epithelial cell cultures

Epidemiological studies suggest that carotenoids may play a role in human breast carcinogenesis. To identify an anticarcinogenic mechanism, a laboratory model for examination of biologic effects is required. Efficacy of tetrahydrofuran (THF) for delivery of beta-carotene to a human mammary epithelial cell line has not been reported, and biologic effects of carotenoids on normal mammary epithelial cells or mammary epithelial cell lines have not been described. In these studies, we examined MCF-10A cells treated with 0.04%, 0.10%, and 0.35% THF (vol/vol) for morphological signs of toxicity and determined effects of THF on cell proliferation over a seven-day period. Cells treated with THF demonstrated a reduction in mean number of cells per dish (p < 0.05) but still underwent a 3.2- to 4.0-fold increase in cell number over the seven days. MCF-10A cells were also treated with a 7 mumol/l solution of beta-carotene and examined for morphological changes and effects on cell growth. Exposure to this concentration of carotenoid did not significantly affect proliferation but did induce the formation of cytoplasmic vacuoles similar to those seen in differentiating mammary epithelial cells. High-performance liquid chromatography analysis revealed a beta-carotene concentration of 0.004 nmol/10(6) cells in the treatment group. The effects of beta-carotene and the non-provitamin A carotenoid canthaxanthin were also examined in the in vitro cultures of primary human mammary epithelial cells obtained from reduction mammoplasties of two individuals. Exposure to these carotenoids induced morphological changes consistent with cellular differentiation and had a dramatic effect on the proliferative life span of these cells. Thus carotenoids may directly affect the proliferative capacity and differentiation of mammary epithelial cells, which may be among the chemoprotective activities of these compounds.

Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk.

The biotransformation of the natural estrogen 17 beta-estradiol (E2) via the C16 alpha-hydroxylation pathway is elevated in patients with breast cancer, in subjects at increased risk for developing breast cancer, and in c-Ha-ras-initiated mouse mammary epithelial cells. To determine whether differences in the extent of E2 C16 alpha-hydroxylation are related to the risk of developing breast cancer, we examined the extent of biotransformation of E2 via the C16 alpha-hydroxylation pathway in the mammary terminal duct lobular units (TDLUs), epithelial organoids that are a presumptive target site of human breast carcinogenesis, and in nontarget component mammary fat tissue. Noninvolved mammary tissue was obtained from four patients undergoing reduction mammoplasty and from four undergoing mastectomy for breast cancer. A radiometric assay that measures 3H2O formation caused by stoichiometric 3H exchange from [C16 alpha-3H]E2 was utilized to compare the relative extent of C16 alpha-hydroxylation in explant cultures of TDLUs and mammary fat. The extent of E2 C16 alpha-hydroxylation was 1.83-fold higher (95% confidence interval [CI] = 1.71-1.97) in the TDLUs from reduction mammoplasty (i.e., "low-risk") patients and 7.96-fold higher (95% CI = 6.38-10.55) in the TDLUs from mastectomy (i.e., "high-risk") patients than in the corresponding values observed in the mammary fat. In the TDLUs obtained from the patients undergoing mastectomy for cancer, the extent of this metabolism was 4.56-fold higher (95% CI = 3.97-5.33) than that observed in TDLUs obtained from reduction mammoplasty patients who did not have cancer. The increase in the extent of C16 alpha-hydroxylation of E2 in the epithelial organoids of the human breast, TDLUs in particular, may be an important factor for breast cancer induction. This upregulation may represent an endocrine biomarker for the risk of developing breast cancer. A larger prospective study is required to confirm the clinical significance of this endocrine biomarker.

Estrogen and progestin effects in human breast carcinogenesis

The influences of estrogen and progestin on human mammary neoplasia are reviewed with a view to identifying what is known about their effects. Estrogens promote growth of established cancer and pharmacological levels of progestins induce remission. In vivo, highest proliferation of histologically normal mammary epithelium occurs in the progestogenic phase of the menstrual cycle or under the progestogenic influence of oral contraceptives. Little additional hard data exist to indicate whether progestins promote or inhibit human mammary carcinogenesis. Effects on proliferation, steroid receptor content and development are discussed together with interpretation of epidemiological data on risk factors that have hormonal components. Progestins may not be the benign or beneficial agents previously supposed, and there are virtually no data to suggest that they are antiestrogenic. It is hypothesized that carcinogenesis may be accompanied by increased sensitivity to estrogen, which provides a growth advantage to the tumor by maximizing use of the low estrogen concentrations encountered in the postmenopausal state.

Biology of the protein kinase C family.

Protein kinase C (PKC) is composed of a family of isozymes that transduce signals of certain hormones, growth factors, lectins, and neurotransmitters. This review addresses the role of PKC in the regulation of cellular proliferation and its disorders. PKC is directly activated in vivo by the second messenger diacylglycerol, a lipid produced by phospholipase C-catalyzed hydrolysis of phosphatidylinositol and polyphosphoinositides. Diacylglycerol activates PKC by reducing the enzyme's requirement for Ca2+. Phorbol ester tumor promoters and related agents potently activate PKC by a mechanism analogous to that of diacylglycerol, providing evidence that PKC activation is a critical event in tumor promotion. However, the role of PKC activation in tumor promotion is not entirely clear. For example, bryostatin is a potent PKC activator that antagonizes phorbol ester-mediated tumor promotion, and mezerein is a second-stage tumor promoter that potently activates PKC. In addition to studies concerned with tumor promotion, studies of oncogene action also indicate a role for PKC in carcinogenesis. A number of plasma membrane-associated oncogene products and related proteins are PKC substrates, and PKC activation leads to induction of the expression of oncogenes that code for nuclear proteins. PKC is implicated in human breast and colon carcinogenesis. Tumor-promoting bile acids activate PKC, and PKC expression studies in rat colonic epithelial cells and human breast cancer cells indicate a positive role for PKC in the proliferation of the cells. Altered expression of PKC in human colon and breast tumors indicates that PKC isozymes may be useful markers for these diseases.