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Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.

We present the case of a 51-year old female patient with acromegaly that was resistant to somatostatin analogs and dopamine agonists. The patient was diagnosed with breast cancer requiring treatment with the anti-estrogen tamoxifen. Prior to initiating the treatment with tamoxifen, the IGF-I level was very high at 415% of the upper limit of normal for the patient's age and sex. During the tamoxifen treatment, the level of IGF-I dropped spectacularly down to normal levels. This observation highlights the effect of an anti-estrogen treatment in certain female patients with acromegaly.

Background Ductal lavage (DL) allows repeat sampling of breast epithelium for serial observation in a chemoprevention setting; however, the reproducibility of duct cannulation, cell yield and cytology has not been addressed. Methods We conducted a Phase 2 trial, wherein high risk women chose tamoxifen treatment or observation following an entry DL procedure. We present data from the non-intervention arm of our study to assess the reproducibility of cannulation, cell yield, and cytologic diagnosis from DL of the same duct at two time-points. Inter-observer variability was assessed by a blinded review of Papanicoloau-stained slides by two cytopathologists. Results Sixty-five women had a successful lavage of 187 ducts at baseline and chose observation; 63/65 (97%) had a successful lavage 6 months later. Successful recannulation of the same duct was accomplished in 63 women (97%) and162 ducts (87%). Total epithelial cell yields ≥100 were obtained from 57/65 women (88%) and 129/187 ducts (69%) at baseline, and 46/63 women (73%) and 80/162 ducts (49%) at both time-points. Cytologic diagnosis was reproducible in 27/63 (43%) women and 77/162 (48%) ducts. Inter-observer variability for cytologic diagnosis between two observers showed good agreement (κ = 0.62). Conclusions Recannulation and lavage of the same duct after a 6 month interval can be achieved with high frequency; however, reproducibility of cell yield and cytologic findings from the same duct is sub-optimal, leading to significant attrition of evaluable subjects. The utility of DL for the serial monitoring of breast epithelium is therefore limited.

Tamoxifen (TAM) ist in der adjuvanten Therapie des Mammakarzinoms ebenso etabliert wie die Strahlentherapie; der optimale Zeitpunkt fur den Beginn der Therapie mit TAM – simultan zur oder sequentiell nach Strahlentherapie – wird kontrovers diskutiert. In dieser Arbeit wird ein Literaturuberblick gegeben. In-vitro-Daten unterstutzen die Vermutung einer antagonistischen Wirkung von TAM auf den Tumor; im Tierexperiment zeigte sich eine synergistische Wirkung. Berucksichtigt man zusatzlich die Modulation der Wirkung von TAM beispielsweise durch Ostrogene oder andere Wachstumsfaktorrezeptoren, erscheint die kombinierte Wirkung von TAM und Bestrahlung zu komplex, um in einem zweidimensionalen, zellularen In-vitro-System untersucht werden zu konnen. Aus klinischer Sicht gibt es zurzeit keinen ausreichenden Anhalt fur eine reduzierte Strahlenwirkung am Tumor durch die simultane im Gegensatz zur sequentiellen Gabe von TAM. Um eine Radioprotektion sicher auszuschliesen, sollten jedoch prospektive, randomisierte klinische Studien mit dieser Fragestellung durchgefuhrt werden. Die aktuelle Literatur zu Interaktionen von Strahlentherapie und TAM ist widerspruchlich, aber klinisch und damit fur die Therapieentscheidung wohl nur von untergeordneter Bedeutung.

Some individuals with estrogen receptor–α (ER-α)-positive breast cancer do not respond to tamoxifen treatment. Increased expression of the ubiquitin ligase CUEDC2 may contribute to this endocrine resistance by reducing theamounts of ER-α (pages 708–714).

Because of previous contradictory results, we reevaluated the effects of tamoxifen on 29 men presenting with idiopathic oligozoospermia. To determine whether a possible increase in sperm concentration might be correlated with an improvement of sperm quality, the hamster ovum penetration (HOP) test and the hypo-osmotic swelling (HOS) test were included as additional tests of sperm function. Patients were treated with tamoxifen (20 mg/day) for 3 months. From 4 weeks until the end of the study, tamoxifen had a significant effect (P0.001) on blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and estradiol (E2). Prolactin (PRL) concentrations were not altered significantly (P0.05). There was no significant improvement (P0.05) of conventional semen parameters (volume, concentration, motility, morphology), and of HOP and HOS test results. The lack of correlation between a rise in hormone levels and improvement of sperm quality suggests that tamoxifen is of questionable value in men with idiopathic oligozoospermia.

CYP2D6 variants and the prediction of tamoxifen response in randomized patients : authors' response

Background/Aims Tamoxifen therapy can cause a 4% decrease in platelet count, yet increases risk of thrombosis. We hypothesized that this decrease was influenced by concentrations of tamoxifen or its metabolites that may lead to changes in platelet function. Methods Candidates for tamoxifen therapy (n=88) participated in a prospective, observational trial. Before and 4 months after tamoxifen treatment, we measured platelet counts (N=88), platelet aggregation (N=17), and plasma concentrations of tamoxifen and its metabolites (N=41). Results Tamoxifen therapy led to a 4% decrease in platelet counts (P= 0.039) in our cohort. This decrease was negatively correlated with plasma concentrations of endoxifen (R2= 0.27, P=0.0006) and 4-hydroxy tamoxifen (R2= 0.22, P=0.003), but not with tamoxifen and N-desmethyl tamoxifen. There were no significant changes in either ADP (13.33±12.3 Ω vs 11.6±11.5 Ω, P= 0.12) or arachadonic acid (9.6±46.1 vs 7.0±37.6 Ω, P=0.19) induced platelet aggregation. Conclusion Decrease in platelet counts after tamoxifen was negatively correlated with endoxifen and 4-hydroxy tamoxifen concentrations, and did not lead to changes in platelet function. Clinical Pharmacology & Therapeutics (2005) 77, P63–P63; doi: 10.1016/j.clpt.2004.12.133

Background/Aims Hot flashes are the most common side effect of tamoxifen treatment. We conducted a prospective observational trial to evaluate factors that influenced hot flash severity after tamoxifen treatment. Methods Hot flashes frequency and severity were recorded in 7-day hot flashes diaries before, and 1, 4, 8, 12 months after tamoxifen treatment in 122 subjects. Hot flashes composit scores were calculated. Demographic information was collected at baseline, and estrogen receptor (ESR1 & 2) genotyping was also performed. Results Pre-menopausal women showed the biggest increase in hot flashes severity, from 5.2±10.5 at baseline to 28.5±51.6 at 4 month (P

Tamoxifen Treatment of Progressive Precocious Puberty in a Patient With McCune-Albright Syndrome † 420