Estrogen sulfotransferase and sulfatase: Roles in the regulation of estrogen activity in human uterine endometrial carcinomas

Abstract

The regulation of estrogen activity through the formation and cleavage of sulfoconjugates of estrogens is known to be related to the progression and metastasis of estrogen-dependent breast carcinomas, but the involvement of sulfoconjugates in the steroid stimulation of endometrial functions and the progression of endometrial adenocarcinomas is not clearly understood yet. Estrogen sulfotransferase (EST) in the uterine endometria during the follicular phase was more active than during the luteal phase, but estrogen sulfate (ES) sulfatase exhibited lower activity during the follicular phase than during the luteal phase. However, ES sulfatase activities in cancerous tissues were lower than those in normal endometria and endometrial adenocarcinoma-derived cells, among which the activity was exceedingly high in Ishikawa cells, suggesting that ES sulfatase in Ishikawa cells contributes to the estrogen-dependent growth of these cells. EST Steroid receptors in the endometrial epithelium are known to be involved in the expression of several genes in response to steroid stimulation of endometrial functions related to the implantation of fertilized eggs, and a failure of the steroid-mediated signal transduction pathway is implicated in the progression of endometrial adenocarcinomas, [2][3][4] as well as of breast carcinomas.5-7) Estrogen is a steroid relevant to the progression of transformed cells, but its active form, 17β-estradiol (E2), is locally generated by several enzymes, such as estrogen sulfotransferase (EST), estrogen sulfate (ES) sulfatase, aromatase, 17β-hydroxysteroid dehydrogenase and so on, since the circulating estrogen in human sera comprises inactive estrone (E1) sulfate.8) Among these enzymes, EST and ES sulfatase in breast carcinomas have been shown to be involved in the regulation of estrogen activity by forming and cleaving the sulfoconjugate of estrogen to inhibit and promote the binding of estrogen to its receptor, respectively. 9, 10) In this connection, inhibition of sulfotransferase by several chlorinated phenol derivatives, such as 6,6-dichloro-4-nitrophenol and hydroxylated polychlorinated biphenyl, has been shown to enhance the activity of endogenous estrogen, and to be probably implicated in human reproductive disorders and an increased incidence of breast carcinomas. 11) On the contrary, environmental xenoestrogens, such as bisphenol, 4-n-octylphenol, 4-n-nonylphenol, and 17α-ethynylestradiol, which have became ubiquitous in the environment and have been shown to cause a decrease in sperm quality and progression of estrogen-dependent cancers by interacting with the estrogen receptor, are converted to their sulfoconjugates by cytosolic sulfotransferase, resulting in detoxification of the chemicals through abolition of their binding ability to the receptor and in facilitation of their removal from the body through an increase in water solubility.12, 13) Thus, the sulfoconjugation of estrogens and related compounds occurring inside cells plays essential roles in the regulation of estrogen rec...

The Biological Roles of Steroid Sulfonation

“…For example, whilst estrogens bind to their genomic estrogen receptors, estrogen sulfates do not bind. This finding is supported by the over-expression of SULT1E1 in cultured human breast carcinoma-derived cells, as well as uterine endometrial Ishikawa cells, which abolish estrogen-stimulated cell proliferation [61,62]. Conversely, increased expression of STS which increases unconjugated (active) steroid levels, leads to enhanced estrogen-stimulated cell proliferation [63].…”

“…SULT1E1 activity is more abundant in normal breast cells lines when compared to cancer cells lines. In cultured carcinoma cells, transfection of SULT1E1 led to effective reductions in estrogen-mediated cell proliferation [61,62]. This can be relevant to polymorphisms in the SULT1E1 gene which have been associated with increased risk of breast cancer and reduced disease free survival [93].…”

Expression of α2,6-sialic acid-containing and Lewis-active glycolipids in several types of human ovarian carcinomas

“…The cancer tissues were homogenized using a homogenizer (Polytron; Kinematica, Luzern, Switzerland) in 0.25 M sucrose, and the microsomal fractions were prepared by centrifugation as previously described (15). The standard assay mixture for microsomal α2,3-and α2,6-sialyltransferases comprised 7.6 nmol nLc 4 Cer, 10 mM MgCl 2 , 5 mM CaCl 2 , 10 mM CMP-sialic acid, 0.3% Triton CF54, 50 mM 4-morpholinoethane sulfonic acidNaOH buffer (pH 6.4), and 50 µg enzyme protein, in a final volume of 50 µl (16,17).…”

“…The primers for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were used as controls. The resulting PCR products were electrophoresed on a 1.5% agarose gel, stained with ethidium bromide, and examined using a UV transilluminator (15).…”

Genetics and pathophysiology of mammalian sulfate biology

“…Reduced expression of SULT2A1 is found in hepatocellular carcinoma cells , whereas SULT1E1 activity is less abundant in breast cancer cell lines when compared to normal breast cell lines (Falany et al, 2002;Tanaka et al, 2003).…”