Steroid Metabolism and Content of Normal and Neoplastic Tissues and Cells

This thesis examines metabolism of steroids, evaluated through conversion rates of precursors (like oestradiol (E2) and testosterone (T)) in "in vitro"' systems. Several long term cell lines derived from the endocrine related tumours of breast, endometrium and prostate were used

Sex steroids, carcinogenesis, and cancer progression

The relationship between sex steroids and cancer has been studied for more than a century. Using an original intact cell analysis, we investigated sex steroid metabolism in a panel of human cancer cell lines, either hormone responsive or unresponsive, originating from human breast, endometrium, and prostate. We found that highly divergent patterns of steroid metabolism exist and that the catalytic preference (predominantly reductive or oxidative) is strictly associated with the steroid receptor status of cells. We explored intra-tissue concentrations and profiles of estrogens in a set of human breast tumors as compared to normal mammary tissues, also in relation to their estrogen receptor status. In particular, we showed that, with hydroxyestrogens representing the majority of all tissue estrogens, concentrations of individual metabolites, as well as their ratios, significantly differ when comparing normal tissue with cancer tissues or when they are related to the overall survival of cancer patients. © 2004 New York Academy of Sciences

Hormone-related tumors : novel approaches to prevention and treatment /

Symposium held on May 1-6, 200

Modulation of oestrogen excretion profiles by adjuvant chemotherapy in pre- and postmenopausal breast cancer

Modulation of steroid status by conventional chemotherapy was studied in 31 breast cancer patients receiving CMF and in 31 age-matched breast cancer patients without any therapy, taken as controls. This was achieved through the study of oestrogen excretion profiles using previously identified parameters and referring not only to classical but also to the "other", namely catechol and unusual, oestrogen metabolites. After CMF treatment the premenopausal patients exhibit a modified excretion pattern, mainly concerning a marked and significant reduction of classical oestrogens, as shown by pattern indices. Because there is evidence that oestriol metabolism is not markedly affected by CMF treatment, such a significant decrease in classical oestrogens must be attributed to the secretory function, presumably ovarian ab origine. To the contrary, after treatment, pattern indices show significantly higher median values in postmenopausal patients. Mean oestriol ratio values also display a significant increase, thus supporting the hypothesis that conventional cytotoxic drugs may act by enhancing oestrogen metabolic rates. In fact, the postmenopausal treated subgroup proved to have significantly higher excretion levels of most of the oestrogens considered to date. Surprisingly, E1 + E1-S fractions were strongly reduced in this subgroup and this leads to the suggestion of an increased steroid metabolic rate by CMF treatment. However, comparing 9 breast cancer patients, when having had both short-term and non-short-term CMF treatment, the effects on steroid excretion patterns appear to arise at an early stage

Soluble and nuclear oestrogen receptor status of advanced endometrial cancer in relation to subsequent clinical prognosis

Both soluble and nuclear oestrogen receptors have been measured in at least two separate sections from 72 endometrial. cancers and 12 normal endometria. Concentration of oestrogen receptor is shown to be, in our hands, more meaningful when expressed per unit DNA than per unit protein, whether for soluble or nuclear receptor. Endometrial cancer cells from the central part of the tumour are shown to be receptor negative more frequently than those from peripheral tumour. Thus, in large cancers, biopsies from different areas are required before a tumour can be correctly designated as receptor positive, heterogeneous or receptor negative. The intratumoral variation of receptor status may relate to poor prognosis, since patients with homogeneous receptor-positive disease survive significantly longer than those with tumours showing either heterogeneous distribution of receptor or homogeneous absence of receptor. Intratumoral variation in receptor status is found to be more common in the group of patients who are within 7 years of their menopause, than in older patient

Intercellular communication and human hepatocellular carcinoma

We have previously reported that gap junction-mediated intercellular communication (GJIC) can be restored in junctionally deficient human prostate epithelial cells, also suggesting that GJIC activity is regulated by estrogen. In the present work, we report studies on sex steroid regulation of GJIC and proliferative activity in both nontumoral (Chang liver, CL) and malignant (HepG2, Huh7) human liver cells. Junctional activity and liver cell growth were measured using the scrape-loading/dye-transfer (SL/DT) and the MTS assay, respectively. Using the SL/DT, only Huh7 cells exhibited a moderate degree of Junctional activity in basic conditions, while neither CL nor HepG2 cells showed functional GJIC. Under exactly the same experimental approach used for prostate studies, we observed that, once again, both estrogen (either estradiol or estrone) and FK induce a significant increase of GJIC in Huh7 cells, while exposure of HepG2 cells to FK produces only a limited rise of Junctional activity in this cell line. However, estrogen induced a significant increase and reduction of the proliferative activity of CL and Huh? cells, respectively, while growth of HepG2 cells was not affected. While the above evidence suggests that estrogens are primarily implicated in growth regulation and communication of both prostate and liver epithelial cells, it also implies that compounds able to restore GJIC in junctionally deficient cells or prevent its disruption in junctionally proficient cells may be used for development of new strategies in the prevention and/or treatment of several human malignancies, including hepatocellular carcinoma (HCC). © 2004 New York Academy of Sciences