The patient was a 55-year-old woman undergoing surgery for T2, N1, M0, stage II B breast cancer in November 1997. UFT and tamoxifen were administered as adjuvant chemotherapy. S-1 and zoledronic acid were then administered for the recurrence of multiple bone metastasis detected in January 2008. A significant improvement was achieved, and a long-term positive effect was confirmed until an exacerbation of bone metastasis in February 2010. S-1 and zoledronic acid therapy have few adverse drug reactions, they promptly manifest their effect, and are favored as a first choice for treating bone metastasis of breast cancer.
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Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.
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The uterine vasculature plays an important role during pregnancy by providing adequate perfusion of the maternal-fetal interface. To this end, substantial remodeling of the uterine vasculature occurs with consequent changes in responsiveness to contractile agents. The purpose of our study was to characterize the vasorelaxant effects of estrogens on vascular smooth muscles of the rat uterine artery during pregnancy and to evaluate the involvement of estrogen receptors (ESR) and nitric oxide synthases (NOS). To do so, we measured NOS expression in the whole uterine and mesenteric circulatory bed by Western blotting. Vasorelaxant effects of 17beta-estradiol (17beta-E(2)) were assessed on endothelium-denuded uterine arteries with wire myographs in the absence and presence of pharmacological modulators [nitro-L-arginine methyl ester (L-NAME), ICI-182780, tamoxifen]. All experiments were performed on arteries from nonpregnant (NP) and late pregnant (P) rats. In the uterine vasculature of the latter group, NOS3 (endothelial NOS) expression was increased, while NOS1 (neuronal NOS) was reduced compared with NP rats. Expression of the NOS2 (inducible NOS) isoform was undetectable in the two groups. Both 17beta-E(2) and 17alpha-E(2) induced uterine artery relaxation, but the latter evoked lower responses. Endothelium-denuded arteries from NP rats showed larger relaxation with 17beta-E(2) than P rats. This larger relaxation disappeared in the presence of L-NAME. The ESR antagonist ICI-182780 did not affect acute relaxation with 17beta-E(2) and 17alpha-E(2). Moreover, membrane-nonpermeant 17beta-E(2):BSA (estradiol conjugated to bovine serum albumin) did not induce any vasorelaxation. Our results indicate that estrogens exert direct acute vasorelaxant effects in smooth muscles of the rat uterine artery that are mediated by mechanisms independent of ESR activation, but with some stereospecificity. Part of this effect, in NP rats only, is due to nitric oxide produced from muscle NOS1.
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Aromatase inhibitors (AIs) are the most effective endocrine treatment for estrogen receptor α-positive (ERα+) postmenopausal breast cancer. Identification of biomarkers that are able to predict AIs responsiveness of patients is a key for successful treatment. The currently used biomarkers for tamoxifen responsiveness, which including ERα as well as progesterone receptor can only predict part of the potential responders to AIs treatment. Sushi domain-containing protein 3 (SUSD3) is a potential novel biomarker of AIs responsiveness. The lack of SUSD3 expression in breast cancer tissue can be an important predictor for non-responsiveness to AI. Here we reviewed the property and function of SUSD3, its usage as a biomarker and the practicability for SUSD3 to become a target for immune therapy. We suggest this protein can be potentially measured or targeted for prevention, diagnostic, and therapeutic purposes for estrogen or progesterone-dependent disorders including breast cancer in women.
Our results showed that raloxifene improves platelet metabolism in healthy postmenopausal women through an increase of the bioavailability of platelet NO by a reduction of iNOS and the beneficial effects on lipid metabolism. This mechanism of action of raloxifene on platelet activity may explain some cardiovascular protective effects of this selective oestrogen receptor modulator.
Patients with estrogen receptor α (ERα)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3'UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3'UTR enhances the transcriptional activity of ERα through the activation of ERα phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3'UTRs increase ERα activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3'UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3'UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer.
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ER(+) breast cancer cell lines expressed considerable PKC-delta but barely detectable levels of PKC-alpha, whereas ER(-) cell lines expressed PKC-alpha but little PKC-delta. ER(+) acquired TAM-R cell lines expressed substantial levels of both PKC-alpha and delta. In clinical samples, high PKC-delta expression correlated to endocrine responsiveness whereas PKC-alpha expression correlated to ER negativity. PKC-delta was an independent predictor of duration of response to therapy. Patients showing a PKC-delta(+)/PKC-alpha(-) phenotype had a six times longer endocrine response than patients with the PKC-delta(+)/ PKC-alpha(+) phenotype (equating to tamoxifen resistance in vitro).