A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer

Rasmussen, Louise Maymann; Zaveri, Nurulain T.; Stenvang, Jan; Peters, Richard H.; Lykkesfeldt, Annè E.

doi:10.1007/s10549-007-9494-y

Cited by 40 publications

(30 citation statements)

References 51 publications

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“…To investigate the contribution of ER to the PRL-and E 2 -stimulated cell proliferation, we used the pure ER antagonist ICI 182 780 (Faslodex, Fulvestrant). ICI 182 780 binds to ER with high affinity and abrogates its transcriptional activity, followed by a rapid degradation of the receptor (Marsaud et al 2003) and hence inhibition of breast cancer cell proliferation (Rasmussen et al 2007). As expected, ICI 182 780 completely abolished E 2 -stimulated proliferation ( Fig.…”

Section: Prlr and Er Expression In Human Breast Cancer Cell Linessupporting

confidence: 63%

Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

Rasmussen¹,

Frederiksen²,

Din³

et al. 2010

Endocrine-Related Cancer

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The pituitary hormone prolactin (PRL) plays an important role in mammary gland development. It was also suggested to contribute to breast cancer progression. In vivo data strongly supported a crucial role of PRL in promoting tumour growth; however, PRL demonstrated only a weak, if any, pro-proliferative effect on cancer cells in vitro. Several recent studies indicated that PRL action in vivo may be influenced by the hormonal milieu, e.g. other growth factors such as 17b-oestradiol (E 2 ). Here, we explored the potential interplay between PRL and E 2 in regulation of gene expression and cell growth. PRL alone induced either a weak or no proliferative response of T47D and BT-483 cells respectively, while it drastically enhanced cell proliferation in E 2 -stimulated cultures. Affymetrix microarray analysis revealed 12 genes to be regulated by E 2 , while 57 genes were regulated by PRL in T47D cells. Most of the PRL-regulated genes (42/57) were not previously described as PRL target genes, e.g. WT1 and IER3. One hundred and five genes were found to be regulated upon PRL/E 2 co-treatment: highest up-regulation was found for EGR3, RUNX2, EGR1, MAFF, GLIPR1, IER3, SOCS3, WT1 and AREG. PRL and E 2 synergised to regulate EGR3, while multiple genes were regulated additively. These data show a novel interplay between PRL and E 2 to modulate gene regulation in breast cancer cells.

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Section: Prlr and Er Expression In Human Breast Cancer Cell Linessupporting

confidence: 63%

Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

Rasmussen¹,

Frederiksen²,

Din³

et al. 2010

Endocrine-Related Cancer

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“…Given that steroid sulfatase inhibitors are effective for inhibiting MCF-7 cell proliferation induced by estrone sulfate, i.e. a substrate for steroid sulfatase (Selcer et al 1997, Rasmussen et al 2007, the effects of BMP6 and BMP7 on steroid sulfatase expression may also contribute to the inhibition of estrogensensitive breast cancer cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Takahashi¹,

Otsuka²,

Miyoshi³

et al. 2008

Journal of Endocrinology

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Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiolinduced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

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“…In vitro studies have examined one such agent, SR 16157 (Fig. 4, compound 3), which is designed as a sulfamatecontaining steroidal STS inhibitor that releases a selective ERa modulator (SERM) upon enzymic reaction with STS (Rasmussen et al 2007). This approach, in theory, will have the potential to inhibit both estrogen biosynthesis and ER action.…”

Section: Dual-targeting Sts Inhibitorsmentioning

confidence: 99%

Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

Purohit¹,

Foster²

2011

Journal of Endocrinology

116

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Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.

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A novel dual-target steroid sulfatase inhibitor and antiestrogen: SR 16157, a promising agent for the therapy of breast cancer

Cited by 40 publications

References 51 publications

Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

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