Steroid Sulphatase

STS is a member of a superfamily of 12 different mammalian sulfatases (89, 90). The gene coding for human STS is located on the distal short arm of the X-chromosome and maps to Xp22.3-Xpter. STS gene is pseudoautosomal and escapes X-inactivation. It has been cloned, characterized, and sequenced (91). On the Y-chromosome, there is a pseudogene for STS, which is transcriptionally inactive as the promoter, and several exons have been deleted. The gene consists of 10 exons and spans 146 kb, with the intron sizes ranging from 102 bp up to 35 kb (92).

Information about the molecular regulation of STS is still limited. It was observed that both basic fibroblast growth factor and IGF-I increase STS activity in a dose- and time-dependent manner in MCF-7 and MDA-MB- 231 breast cancer cells (93). Moreover, both cytokines TNFa and IL-6 upregulate STS enzyme activity in MCF-7 breast cancer cells. However, this upregulation appears to be post-translationally mediated rather than occurring via any changes in gene transcription or mRNA stability (94). Interestingly, STS mRNA levels decreased when MCF-7 breast cancer cells were treated with the progestagen; Promegestone (R-5020) (95). In contrast, it was observed that exposure of MCF-7 and MDA-MB-231 breast cancer cells to the progestagen; medroxypro-gesterone acetate, stimulated STS activity in these cells (93).

Immunohistochemistry and STS mRNA expression of laser-captured micro-dissected samples were also used to examine the location of STS within breast tumours (82). STS immunoreactivity was detected in the cytoplasm of cancer cells with STS mRNA expression being detected in micro-dissected carcinoma cells but not in stromal cells.

STS hydrolyzes circulating oestron sulphate (E1-S) to E1 in various human tissues (96, 97, 98, 99, 100, 101) and acts on DHEAS which is considered the most abundant steroid secreted by the adrenal cortex reducing it to DHEA by the removal of the sulfate group. DHEA in turn can undergo reduction to Adiol (102) which is known to have affinity for ER and can stimulate the growth of ER positive breast cancer cells in vitro (75, 103). This finding shows that Adiol does not need to be converted to an oestrogen in order to stimulate tumour growth. Further studies have revealed that DHEA and Adiol can directly activate the ER and stimulate the proliferation of breast cancer cells (104). Moreover, recent research has shown that DHEAS, DHEA, and Adiol can stimulate the proliferation of breast cancer cells in vitro and induce mammary tumours in vivo (105) and their ability to do so is blocked by the ER antagonist nafoxidene, but not by aromatase inhibitors. These results provide strong evidence that the stimulation of cell growth by DHEAS occurs via an aromatase-independent pathway that can be potentially blocked by an STS inhibitor.

The STS mRNA expression in malignant breast tissue seems to be significantly higher than in normal tissue (106). This finding is consistent with the higher STS enzymatic activity that has been detected in malignant breast tissue (22, 107).

STS mRNA expression was found to be an independent prognostic indicator in predicting relapse-free survival, with high levels of expression being associated with larger tumour size, lymph node metastasis, increased risk of recurrence, and poor prognosis (28, 82, 107, 108).

It was also reported that the association between STS mRNA expression and prognosis applied only to ER positive tumours. Recently, our group demonstrated a significant correlation between High levels of STS mRNA and poor survival (Figure 4). In addition, STS mRNA levels were correlated with aromatase mRNA levels (109). Interestingly, high STS mRNA expression was observed to be associated with a poor prognosis in both pre- and postmenopausal women. This finding led to the suggestion that even in premenopausal women, intratumoral oestrogen synthesis may play an important role in the growth of breast tumours.

Finally, both steroidal and non-steroidal STS inhibitors have been recently developed and seem to be effective in depressing the proliferation of oestrogen-dependent MCF-7 cells (110). Since oestrogen formation from E1S and DHEAS (STS pathway) cannot be blocked by aromatase inhibitors, STS is thought to be a new molecular target for the treatment of oestrogen-dependent tumour post-SERM and/or aromatase inhibitors (111). However, accurate determination of STS and ER levels in tumour specimens is required in order to achieve the maximum potential benefits from STS inhibitors. Phase III clinical trials will determine the usefulness of such drugs.

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