Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen. 相似文献
G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER−/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs. 相似文献
Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.
Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.
Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available. 相似文献
The ovarian and pituitary functions of 64 operable breast cancer patients undergoing adjuvant therapy with cytotoxic chemotherapy
and/or tamoxifen were investigated. The post menopausal patients, divided into 3 treatment groups, one with tamoxifen alone,
one with tamoxifen and chemotherapy and the other with chemotherapy alone had serum estradiol 17-β (E2) and progesterone levels
lower than the evaluable limits. Although there was no significant difference in the level of estrone sulfate (E1-S) between
these three groups, the level of lutainizing hormone (LH) and follicle stimulating hormone (FSH) in the patients treated with
tamoxifen alone and tamoxifen and chemotherapy were significantly lower than those treated with chemotherapy alone. The decrease
in gonadotropin levels induced by tamoxifen treatment was reversible as it appeared after the initiation of tamoxifen and
recovered after its cessation. In the premenopausal patients, a group treated with tamoxifen and chemotherapy had significantly
higher E1-S, E2 and progesterone levels and significantly lower gonadotropin levels than a group treated with chemotherapy
alone or one treated with a cyclophosphamide regimen. These increases in the levels of estrogen and progesterone were also
reversible, and induced by tamoxifen. Thus, adjuvant endocrinochemotherapy causes profound alteration in the hypothalamo-pituitary-ovarian
axis and therefore, monitoring a variety of hormonal levels is thought to be necessary for assessing the consequences of adjuvant
therapy in breast cancer patients, especially in premenopausal patients using tamoxifen. 相似文献
BACKGROUND: The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. METHODS: Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. RESULTS: A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. CONCLUSIONS: The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is >3 mm, hysteroscopy and biopsy is the optimal method of detecting intrauterine pathology in women with breast cancer who are about to commence endocrine treatment. 相似文献
The parameters that characterize the intricate water diffusion in tumors may serve to reveal their distinct pathology. Specifically, the application of diffusion magnetic resonance imaging (MRI) can aid in characterizing breast cancer, as well as monitoring response to therapy. We present here a non-invasive, quantitative MRI investigation, at high spatial resolution, of water diffusion in hormonal dependent MCF7 breast tumors implanted orthotopically in immunodeficient mice. Distinctive MRI protocols were designed in this study, utilizing a broad range of diffusion times and diffusion gradient strengths. Application of these protocols allowed water diffusion in the tissue extracellular and intracellular compartments to be distinguished, and the effect of restricted diffusion and water exchange on the water diffusion in these compartments to be evaluated. Pixel-by-pixel analysis yielded parametric maps of the estimated volume fraction and apparent diffusion coefficient of each compartment. The diffusion of the water in the extracellular microenvironment was approximately two fold slower than that of free water, and in the intracellular compartment was about one order of magnitude slower than that of free water and demonstrated restriction of water diffusion at long diffusion times. Mapping of the water fraction in each compartment was further employed to monitor changes during tumor progression and to assess tumor response to hormonal manipulation with a new antiestrogenic drug, tamoxifen methiodide (TMI). It was found that, in parallel to the growth arrest by this drug, the volume fraction of the slowly diffusing water increased, suggesting a TMI-induced cell swelling. This study can serve as a basis for extending diffusion breast MRI in the clinical setting. 相似文献
Summary Clinical results of tamoxifen (Nolvadex-ICI) monotherapy in 44 premenopausal women with advanced breast cancer have been reviewed. Objective tumor regression was achieved in 12 (27%) patients and a further 10 (22%) were classified as stabilized. Median duration of response was 12.7 months at the time of analysis. Greatest benefits occurred in soft tissue dominant and receptor-positive tumors, but there was no correlation between tumor response and other clinical manifestations of estrogen deprivation (e.g. menstrual disturbance, hot flushes).The benefits of conventional doses of tamoxifen do not therefore appear to be influenced by menopausal status and compare favorably to achievements reported after surgical oophorectomy. 相似文献