Elevated steroid sulfatase expression in breast cancers

Utsumi, Toshiaki; Yoshimura, Nagahisa; Takeuchi, Shinji; Maruta, M.; Maeda, Kotaro; Harada, Nobuhiro

doi:10.1016/s0960-0760(00)00060-1

Cited by 99 publications

(69 citation statements)

References 27 publications

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“…STS activity was found to be present at a considerably higher level than aromatase and aromatase activity was only detectable in about 60% of tumors [13,14]. Recently STS mRNA expression has been measured in breast tumors and shown to be at a much higher level than aromatase mRNA expression [15]. Such studies also revealed that STS mRNA expression is higher in malignant than in normal breast tissue.…”

Section: Sts In Breast Tumorsmentioning

confidence: 98%

Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer

et al. 2007

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Key Words. Breast cancer • Estrogen • Estrone sulfate • Steroid sulfatase • Sulfatase inhibitor LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Discuss the role of steroid sulfatase in regulating estrogen production in postmenopausal women.2. Describe the potential of steroid sulfatase inhibition in cancer therapy.3. Discuss a potential new endocrine therapy for patients progressing on aromatase.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTInhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mRNA expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women.

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Section: Sts In Breast Tumorsmentioning

confidence: 98%

Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer

et al. 2007

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“…The importance of E 1 S and STS in postmenopausal breast cancer is highlighted by the following facts: E 1 S is the most abundant circulating oestrogen in postmenopausal women, it has a considerably longer half-life in plasma compared with oestrone, levels of E 1 S in breast tumors are considerably higher than in the plasma, and the activity of STS is 50-200 times that of aromatase (Pasqualini et al 1996, Pasqualini & Chetrite 2005. STS mRNA expression is negatively correlated with the clinical outcome of breast cancer patients (Utsumi et al 2000, Miyoshi et al 2003 and it has been proposed that the sulfatase pathway is more important than the aromatase route, since aromatase mRNA expression has no diagnostic value .…”

Section: Sulfatase and Sulfotransferasementioning

confidence: 99%

Phytoestrogens and breast cancer –promoters or protectors?

Rice¹,

Whitehead²

2006

Endocr Relat Cancer

165

119

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The majority of breast cancers are oestrogen dependent and in postmenopausal women the supply of oestrogens in breast tissue is derived from the peripheral conversion of circulating androgens. There is, however, a paradox concerning the epidemiology of breast cancer and the dietary intake of phytoestrogens that bind weakly to oestrogen receptors and initiate oestrogendependent transcription. In Eastern countries, such as Japan, the incidence of breast cancer is approximately one-third that of Western countries whilst their high dietary intake of phytoestrogens, mainly in the form of soy products, can produce circulating levels of phytoestrogens that are known experimentally to have oestrogenic effects. Indeed, their weak oestrogenicity has been used to advantage by herbalist medicine to promote soy products as a natural alternative to conventional hormone replacement therapy (HRT). Such usage could increase in light of recent evidence that long-term HRT usage may be associated with an increased risk of breast cancer with a consequent reduction in prescription rates. So, are phytoestrogens safe as a natural alternative to HRT and could they be promoters or protectors of breast cancer? If they are promoters, then we must assume that it is due to their oestrogenic effect. If they are protectors, then other actions of phytoestrogens, including their ability to inhibit enzymes that are responsible for converting androgens and weak oestrogens into oestradiol, must be considered. This paper addresses these questions by reviewing the actions of phytoestrogens on oestrogen receptors and key enzymes that convert androgens to oestrogens in relation to the growth of breast cancer cells. In addition, it compares the experimental and epidemiological evidence pertinent to the potential beneficial or harmful effects of phytoestrogens in relation to the incidence/progression of breast cancer and their efficacy as natural alternatives to conventional HRT.

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“…Expression of STS mRNA in malignant breast tissue is much higher than in the normal breast and also considerably higher than aromatase mRNA expression (15). Three studies have now confirmed that expression of STS mRNA in ER-positive breast tumors is an independent prognostic indicator in predicting relapse-free survival, with higher levels of expression being associated with a poor prognosis (16 -18).…”

mentioning

confidence: 99%

Phase I Study of STX 64 (667 Coumate) in Breast Cancer Patients: The First Study of a Steroid Sulfatase Inhibitor

Stanway

Purohit

Woo

et al. 2006

Clinical Cancer Research

219

158

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Purpose: Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties. Experimental Design: STX64 (667 Coumate), a tricylic coumarin-based sulfamate that irreversibly inhibits STS activity, was selected for entry into the first phase I trial of a STS inhibitor in postmenopausal women with breast cancer. STX64 was administered orally (nine patients at 5 mg and five patients at 20 mg) as an initial dose followed 1week later by 3 Â 2 weekly cycles, with each cycle comprising daily dosing for 5 days followed by 9 days off treatment. Blood and tumor tissue samples were collected for the assessment of STS activity and serum was obtained for steroid hormone measurements before and after treatment. Results: The median inhibition of STS activity by STX64 was 98% in peripheral blood lymphocytes (PBL) and 99% in breast tumor tissue at the end of the 5-day dosing period. As expected, serum concentrations of estrone, estradiol, androstenediol, and DHEA all decreased significantly from pretreatment levels. Unexpectedly, androstenedione and testosterone concentrations also decreased. Four patients, all of whom had previously progressed on aromatase inhibitors, showed evidence of stable disease for 2.75 to 7 months. The drug was well tolerated with only minor drug-related adverse events recorded. Conclusion: STX64 is a potent, well-tolerated STS inhibitor. It inhibits STS activity in PBLs and tumor tissues and causes significant decreases in serum concentrations of steroids with estrogenic properties.

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Elevated steroid sulfatase expression in breast cancers

Cited by 99 publications

References 27 publications

Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer

Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer

Phytoestrogens and breast cancer –promoters or protectors?

Phase I Study of STX 64 (667 Coumate) in Breast Cancer Patients: The First Study of a Steroid Sulfatase Inhibitor

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