Endocrine disruptors (EDs) and hormone-dependent cancers: Correlation or causal relationship?

The selective increase in the incidence of hormone-dependent cancers (breast, prostate, testicular) in industrialized countries is associated with the increasing number of endocrine disruptors (EDs) in the environment and raises questions about the role of EDs in mammary carcinogenesis. Answering these questions is difficult because the number of EDs is large and varies with time. Moreover hormonal carcinogenesis is multifactorial and progresses slowly and in stages.

Cathepsin D stimulates the activities of secreted plasminogen activators in the breast cancer acidic environment.

Two proteases cathepsin D (cath D) and urokinase plasminogen activator (uPA) are tissue markers associated with an increased risk of metastasis in breast cancer. We investigated whether cath D, the major aspartyl protease overexpressed by breast cancer cells can trigger a proteolytic cascade via activation of plasminogens at the extracellular pH measured in hypoxic tumors. The effects of the aspartyl protease inhibitor pepstatin on the plasminogen activator (PA) system were analysed by conditioning media of human MDA-MB231 breast cancer cells at pH 6.

[Bisphenol A and hormone-dependent cancers: potential risk and mechanism].

Being concerned by the increasing incidence of breast, prostate and testicular cancers, we overviewed the literature on the potential carcinogenic effect of endocrine disruptors (ED). It is extremely difficult to obtain the epidemiological proof of a carcinogenic effect of one ED in human for multi-factorial diseases and the high number of confusing factors. However, many experimental studies in rodents on bis-phenol A (BPA) and its assay in human blood and urine, strongly suggest that BPA might increase the risk of hormone dependant cancers.

[Endocrine disruptors: are they carcinogens?].

Concerned with the high incidence of breast and prostate cancers in industrialized countries, including France, we reviewed the literature and national reports on the potential carcinogenic effects of several endocrine disruptors (ED) present in the environment. We examine why it is extremely difficult to obtain clear proof of a carcinogenic effect of ED in humans. Yet the results of several independent studies strongly point to such a carcinogenic effect, particularly in the case of hormone-dependent cancers.

The role of sex steroid receptors on lipogenesis in breast and prostate carcinogenesis: a viewpoint.

Cancer cells require both nutrients and mitogens to multiply and survive in the unfavorable microenvironment of solid tumors or metastases before angiogenesis. Most cancer cells do not use fatty acids (FA) from the circulation but synthesize them in situ especially to make membranes and lipid signals required for continuously dividing cells. Three lipogenic enzymes are overexpressed, induced by sex steroid hormones and responsible for the in situ increased lipogenesis in cancer cells.

[How to reduce the incidence of breast cancer].

The incidence of breast cancer is rising in all industrialized countries. In France, with 41,000 new cases and 11,000 deaths per year, breast cancer is still the first cause of death from cancer in women. Genetic familial breast cancer is rare (only-2% due to mutated BRCA1/2 genes).

[Hormonal carcinogenesis in women: from mechanisms to prevention].

In spite of the explosion of basic knowledge, breast cancer remains a major problem of public health. Basic endocrinology was at the origin of the first targeted therapy in cancer with the anti-estrogens. Continuous breast cancer cell lines helped to specify the mechanism of the mitogenic activity of estrogens, the basis of their tumour promoter activity.

Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis.

Progestins increase the risk of breast cancer in the hormone therapy of menopause, and progesterone receptor-induced fatty acid synthase (FAS) is a potential therapeutical target of breast cancer. In a first attempt to specify in which lesions at risk of breast cancer progestins might be acting, we have compared the progesterone receptor (PR) and FAS expression in preinvasive breast lesions and in adjacent "normal" mammary glands. We used archive paraffin-embedded tissues from 116 patients, with 164 lesions of increasing histological risk from nonproliferative "benign" breast disease (BBD) to in situ breast carcinomas.

Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.

The lysosomal aspartic protease cathepsin D (cath-D) is over-expressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Cath-D over-expression stimulates tumorigenicity and metastasis.

Increased estrogen receptor betacx expression during mammary carcinogenesis.

Identification of proteins that markedly vary during early steps of mammary carcinogenesis may help to understand its pathophysiology and to develop a prevention strategy. The expression of total estrogen receptor beta (ERbeta) protein and of its COOH-terminally spliced variant ERbetacx (or ERbeta2) was compared in 43 invasive breast cancers and in 39 adjacent normal mammary glands and 26 ductal carcinoma in situ (DCIS). Thirty-six breast cancers were ER positive by radioligand binding assay.

Estrogen receptor beta (ER beta) level but not its ER beta cx variant helps to predict tamoxifen resistance in breast cancer.

The antiestrogen tamoxifen, a major endocrine therapy of estrogen receptor (ER)-positive breast cancer, is nevertheless inefficient in 30 to 40% of cases for unknown reasons. We retrospectively studied 50 ER-positive primary breast carcinomas. All of the patients had received tamoxifen as the only adjuvant therapy.

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells.

Overexpression of cathepsin-D in primary breast cancer has been associated with rapid development of clinical metastasis. To investigate the role of this protease in breast cancer growth and progression to metastasis, we stably transfected a highly metastatic human breast cancer cell line, MDA-MB-231, with a plasmid containing either the full-length cDNA for cathepsin-D or a 535 bp antisense cathepsin-D cDNA fragment. Clones expressing antisense cathepsin-D cDNA that exhibited a 70-80% reduction in cathepsin-D protein, both intra- and extracellularly compared to controls, were selected for further experiments.

Procathepsin D interacts with prosaposin in cancer cells but its internalization is not mediated by LDL receptor-related protein.

The cell surface binding, endocytosis, and lysosomal routing of procathepsin D (procath-D) in cancer cells are mostly independent of the mannose-6-phosphate (M6P) receptors. In an attempt to define the receptor involved, we intracellularly cross-linked procath-D with a 68-kDa protein that we identified with specific antibodies as prosaposin in human breast and ovarian cancer cell lines. In cancer cells, this protein-protein interaction was resistant to ammonium chloride or M6P treatment, indicating that it was independent of the M6P receptors.

Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells.

Fibulin-1 is an extracellular matrix protein induced by estradiol in estrogen receptor (ER) positive ovarian cancer cell lines. Alternative splicing of fibulin-1 mRNA results in four different variants named A, B, C and D that may have distinct biological functions. We studied the relative expression of fibulin-1 mRNA variants and their estrogen regulation in human ovarian cancer cells.