Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors.

Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ∼50% of ERα-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERα-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERα-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERα-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERα-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH1A1 (a marker of pluripotency in epithelial cancers which is absent in normal breast tissue) is increased in relapsing tumors, with a concurrent modification of its intra-cellular localization. Our data could be of value in the discrimination of patients susceptible to develop tamoxifen resistance and in the selection of optimized patient-tailored therapies.

Immunohistochemical study of pElk-1 expression in human breast cancer: association with breast cancer biologic profile and clinicopathologic features.

BACKGROUND: Recently an increased interest on Elk1 protein and its role in breast cancer evolution has been noted. This protein is an element of the Ets family of transcription factors and it has been involved in a number of important cell processes through the activation of different genes, in a number of normal tissues as well as in many malignancies. METHODS: One hundred and seventy (n = 170) cases of operable breast cancer (invasive ductal, lobular and mixed type breast carcinomas) were randomly selected and investigated for the expression of pElk-1, Ki-67 and Cyclin D1 using immunohistochemistry. Our findings were correlated with tumors' clinicopathologic data and biologic profile. RESULTS: Activated Elk1 is positively associated with ER (p-value: 0.018) and also shows a positive association of with Cyclin D1 (p-value: <0.001). No relationship was noted between pElk1 and Ki67 (p-value: 0.213). Luminal A and B Her-2 negative breast cancer subtypes were showing greater pElk-1 immunoreactivity compared to Her-2 and Basal breast cancer subtypes, and also a higher staining intensity. No association of the molecule with other clinicopathologic characteristics (tumor size, stage, histological type or lymph node metastases) or disease adverse events (local recurrence, metastasis or death) was evidenced. CONCLUSIONS: Our findings offer a new perspective for the role of pElk-1 in breast neoplasia suggesting a direct relation of this molecule to tumor biology and a putative target of personalized breast cancer therapies, although its prognostic/discriminant role is not supported.

Sleeve gastrectomy plus side-to-side jejunoileal anastomosis for the treatment of morbid obesity and metabolic diseases: a promising operation.

BACKGROUND: The continuing need for simple, safe, and effective procedures led us to design a new operation for treating morbid obesity. METHODS: Thirty-two patients underwent our novel procedure, sleeve gastrectomy plus side-to-side jejunoileal anastomosis (SG plus), and were followed for 6 to 24 months. A matched cohort of 32 patients underwent sleeve gastrectomy over the same period and was used as the control group. Weight loss, comorbidity outcomes, and the duodenum to cecum transit time after a gastrografin swallow, performed at postoperative day 4, were compared. RESULTS: There were no deaths and no major perioperative complications. Three patients developed long-term complications requiring surgical intervention (intestinal obstruction, nausea-vomiting, and hypoalbuminemia). In the SG plus group, a 77.8 % excess weight loss was achieved at 12 months postoperatively, which was significantly better (p < 0.01) than the 67 % observed in the control group. The comorbidity outcomes, particularly diabetes resolution, were also significantly superior in the SG plus patients. The duodenum to cecum transit time of 11 min in the SG plus group was significantly shorter (p < 0.01) than the 31 min observed in the control group. CONCLUSIONS: Sleeve gastrectomy plus side-to-side jejunoileal anastomosis appears to be a simple, considerably safe, and effective procedure for treating obesity and its metabolic comorbidities.

Is there any benefit from sentinel lymph node biopsy using the combined radioisotope/dye technique in breast cancer patients with clinically negative axilla?

OBJECTIVE: We evaluated the eventual benefits from sentinel lymph node biopsy (SLNB) in comparison with axillary lymph node dissection (ALND) using a combined radioisotope/dye technique versus dye alone in breast cancer patients. METHODS: SLNB was performed in 501 breast cancer patients (250 patients with dye alone and 251 with combined technique). Patients were divided in three groups: (A) clinical stage T1,2N0 (SLNB followed by ALND only in cases with positive histology), (B) clinical stage T1,2N0 (SLNB followed by ALND), and (C): advanced clinical stage (SLNB immediately followed by ALND). The incidence of recurrences and surgery morbidity was comparatively evaluated. RESULTS: The overall successful identification rate in patients of groups A and B was 97.7% (95.3% with dye and 99.3% with dye and isotope, P = 0.04) and in patients of group C 96.1% (93.3% with dye and 1000% with the combined technique, P = 0.02). The false-negative rate did not reach statistical significance between groups. Although locoregional recurrence rate was similar in groups A and B (less than 1.88%) the distant metastasis rate was significantly lower in group A (0.9 vs. 6.6%, P = 0.04). Arm edema was significantly more frequent in group B (0 vs. 5.3%, P = 0.02). CONCLUSION: The combined technique, improves the ID rate of SLNs in patients with breast cancer. The recurrence rate in the axilla was negligible and the metastasis-free rate was better in patients treated with SLNB alone, which further supports the concept that ALND has no clinical relevance and adds nothing more than morbidity to breast cancer patients with clinically node-negative disease.