BBA - Reviews on Cancer (v.1654, #2)

Classical tumour suppressor genes are thought to require mutation or loss of both alleles to facilitate tumour progression. However, it has become clear over the last few years that for some genes, haploinsufficiency, which is loss of only one allele, may contribute to carcinogenesis. These effects can either be directly attributable to the reduction in gene dosage or may act in concert with other oncogenic or haploinsufficient events. Here we describe the genes that undergo this phenomenon and discuss possible mechanisms that allow haploinsufficiency to display a phenotype and facilitate the pathogenesis of cancer.
Keywords: Haploinsufficiency; Tumour suppressor gene; Mutation; Breast cancer; Calorectal cancer; Prostate cancer; Leukemia;

It is well established that increased exposure to estradiol (E2) is an important risk factor for the genesis and evolution of breast tumors, most of which (approximately 95–97%) in their early stage are estrogen-sensitive. However, two thirds of breast cancers occur during the postmenopausal period when the ovaries have ceased to be functional. Despite the low levels of circulating estrogens, the tissular concentrations of these hormones are significantly higher than those found in the plasma or in the area of the breast considered as normal tissue, suggesting a specific tumoral biosynthesis and accumulation of these hormones. Several factors could be implicated in this process, including higher uptake of steroids from plasma and local formation of the potent E2 by the breast cancer tissue itself. This information extends the concept of ‘intracrinology’ where a hormone can have its biological response in the same organ where it is produced. There is substantial information that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of E2 from circulating precursors. Two principal pathways are implicated in the last steps of E2 formation in breast cancer tissues: the ‘aromatase pathway’ which transforms androgens into estrogens, and the ‘sulfatase pathway’ which converts estrone sulfate (E1S) into E1 by the estrone-sulfatase. The final step of steroidogenesis is the conversion of the weak E1 to the potent biologically active E2 by the action of a reductive 17β-hydroxysteroid dehydrogenase type 1 activity (17β-HSD-1). Quantitative evaluation indicates that in human breast tumor E1S ‘via sulfatase’ is a much more likely precursor for E2 than is androgens ‘via aromatase’.Human breast cancer tissue contains all the enzymes (estrone sulfatase, 17β-hydroxysteroid dehydrogenase, aromatase) involved in the last steps of E2 biosynthesis. This tissue also contains sulfotransferase for the formation of the biologically inactive estrogen sulfates. In recent years, it was demonstrated that various progestins (promegestone, nomegestrol acetate, medrogestone, dydrogesterone, norelgestromin), tibolone and its metabolites, as well as other steroidal (e.g. sulfamates) and non-steroidal compounds, are potent sulfatase inhibitors. Various progestins can also block 17β-hydroxysteroid dehydrogenase activities. In other studies, it was shown that medrogestone, nomegestrol acetate, promegestone or tibolone can stimulate the sulfotransferase activity for the local production of estrogen sulfates. All these data, in addition to numerous agents which can block the aromatase action, lead to the new concept of ‘Selective Estrogen Enzyme Modulators’ (SEEM) which can largely apply to breast cancer tissue. The exploration of various progestins and other active agents in trials with breast cancer patients, showing an inhibitory effect on sulfatase and 17β-hydroxysteroid dehydrogenase, or a stimulatory effect on sulfotransferase and consequently on the levels of tissular levels of E2, will provide a new possibility in the treatment of this disease.
Keywords: Progestin; 17β-Hydroxysteroid dehydrogenase; Estradiol;