Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice
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Cre recombinase
Bone remodeling
Raloxifene
Toremifene
Antiestrogen
Endometrial hyperplasia
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Selective estrogen receptor modifiers (SERMs) are used chronically in the treatment of breast cancer and osteoporosis but some patients become resistant, at which point second-line SERMs are considered as options. Because the use of SERMs is increasing and breast cancer is so common, we tested the hypothesis that treatment with SERMs can induce cross-resistance to other SERMs. We used three cultured breast carcinoma cell lines (MCF-7, ZR-75-1, and T47D) which are estrogen-receptor-positive (ER+) and are prone to developing resistance to hormonal treatment. Cell lines were exposed to increasing doses of raloxifene. Raloxifene-resistant clones were selected and tested for cross-resistance to tamoxifen. Compared to untreated cells, raloxifene-resistant clones showed an increased IC50 (reduced potency) of about 15,000-fold with no apparent change in maximal inhibition of cell growth. These same raloxifene-resistant clones were also about 15-fold more resistant to the growth-inhibiting effects of tamoxifen. While the resistance to tamoxifen is considerably less marked (1000-fold less), it is large enough to raise the question as to whether patients who become resistant to raloxifene will benefit by switching to tamoxifen or vice versa.
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Endocrine therapy that targets the estrogen receptor (ER) is a standard of care for the treatment of postmenopausal women with ER-positive breast cancer. The selective ER modulator (SERM) tamoxifen has been in use for the treatment of advanced breast
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Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting breast epithelial cell proliferation. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium because of liganded ER-activating target genes in these different cell types. Several novel antiestrogen compounds have been developed that are also selective ER modulators (SERMs) but that have a reduced agonist profile on breast and gynecological tissues. These SERMs offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for three first-generation SERMs (toremifene, droloxifene, idoxifene), which are related to the triphenylethylene structure of tamoxifen. In Phase II trials in a total of 263 patients resistant to tamoxifen, the median objective response rate to these SERMs was only 5% (range, 0-15%), with stable disease for > or =6 months in an additional 18% (range, 9-23%). As first-line therapy for advanced breast cancer, the median response rate was 31% (range, 20-68%) with a median time to progression of 7 months. Randomized Phase III trials for toremifene and idoxifene in more than 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the structurally distinct second- and third-generation SERMs (raloxifene, arzoxifene, EM-800, and ERA-923), although a similarly low median response rate of 6% (range, 0-14%) was seen in Phase II trials in tamoxifen-resistant patients. It remains unclear whether any clinical advantage exists for second- and third-generation SERMs over tamoxifen as first-line therapy. With the emergence of potent aromatase inhibitors (AIs) that are superior to tamoxifen, the clinical questions in advanced disease have shifted to which antiestrogen (including SERMs) may be effective following failure of AIs, and whether any merit exists for combined AI/SERM therapy. The main advantage for SERM therapy probably remains in early stage-disease (adjuvant therapy or prevention), in which the estrogenic effects on bone and reduced gynecological side effects may prove more beneficial than either tamoxifen or AI. The issue is whether the current clinical data for SERMs in advanced breast cancer are sufficiently strong to encourage that further development.
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Abstract As a daily physiological mechanism in bone, microdamage accumulation dissipates energy and helps to prevent fractures. However, excessive damage accumulation might bring adverse effects to bone mechanical properties, which is especially problematic among the osteoporotic and osteopenic patients treated by bisphosphonates. Some pre-clinical studies in the literature applied forelimb loading models to produce well-controlled microdamage in cortical bone. Ovariectomized animals were also extensively studied to assimilate human conditions of estrogen-related bone loss. In the present study, we combined both experimental models to investigate microdamage accumulation in the context of osteopenia and zoledronate treatment. Three-month-old normal and ovariectomized rats treated by saline or zoledronate underwent controlled compressive loading on their right forelimb to create in vivo microdamage, which was then quantified by barium sulfate contrast-enhanced micro-CT imaging. Weekly in vivo micro-CT scans were taken to evaluate bone (re)modeling and to capture microstructural changes over time. After sacrifice, three-point-bending tests were performed to assess bone mechanical properties. Results show that the zoledronate treatment can reduce cortical microdamage accumulation in ovariectomized rats, which might be explained by the enhancement of several bone structural properties such as ultimate force, yield force, cortical bone area and volume. The rats showed increased bone formation volume and surface after the generation of microdamage, especially for the normal and the ovariectomized groups. Woven bone formation was also observed in loaded ulnae, which was most significant in ovariectomized rats. Although all the rats showed strong correlations between periosteal bone formation and microdamage accumulation, the correlation levels were lower for the zoledronate-treated groups, potentially because of their lower levels of microdamage. The present study provides insights to further investigations of pharmaceutical treatments for osteoporosis and osteopenia. The same experimental concept can be applied in future studies on microdamage and drug testing.
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Tamoxifen is a selective oestrogen receptor modulator (SERM) with anti-oestrogenic properties in the breast and oestrogenic effects in tissues such as bone and the cardiovascular system. It is an excellent breast cancer drug for all stages of the disease. Its SERM profile makes it a valuable alternative to hormone replacement therapy, especially for women at high risk of breast cancer. Tamoxifen, however, increases the incidence of benign and malignant lesions of the uterus. Secondary prevention of these, early detection and treatment, is feasible but not cost-effective in breast cancer patients because potential endometrial risks do not outweigh beneficial effects in the breast. This may be different in healthy women with an as yet unknown benefit on breast cancer mortality. We review the literature on the importance of tamoxifen's endometrial lesions and balance available evidence on whether and how best to screen them. In a subset of tamoxifen users it seems advisable to assess the uterine cavity prior to intake with a yearly endometrial assessment as pointed out, starting 3 years after initiation of treatment. In most cases there is endometrial thickening on ultrasonographic assessment and additional tests such as hydrosonography or hysteroscopy are required to confirm an empty atrophic uterus as remains the case in most asymptomatic women on tamoxifen. Newer compounds, such as raloxifene, have a similar SERM profile to tamoxifen but are neutral on the uterus. This has recently been proven by 3 years of endometrial follow-up data. Longer endometrial safety will hopefully confirm these early findings. Whether other SERMs in development are better, and which of them is better for the breast, is to be demonstrated in ongoing studies.
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Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and Drug Administration to reduce the incidence of breast cancer in high-risk women. Despite tamoxifen's antiestrogenic effects in breast tissue, it exhibits paradoxical estrogenic effects in other tissues in the body. These effects result in the maintenance of bone mineral density, but a three- to fourfold increase in endometrial cancer in postmenopausal women. Additionally, tamoxifen can result in troublesome hot flashes and serious thromboembolic events. For this reason, current research is focusing on new agents that may maintain the beneficial effects of tamoxifen while reducing its adverse effects. Raloxifene (Evista) is another SERM, approved for the prevention of osteoporosis in postmenopausal women and now being compared with tamoxifen in an ongoing breast cancer prevention trial. Like tamoxifen, raloxifene is associated with hot flashes and thromboembolic events, but its association with the risk of endometrial cancer is unknown. A number of new SERMs are in preclinical or clinical development in an attempt to improve upon the safety profile of tamoxifen. Additionally, selective aromatase inhibitors are being examined in the early breast cancer setting.
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