The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer.

Antiestrogen-resistant and triple-negative breast tumors pose a serious clinical challenge because of limited treatment options. We assessed global gene expression changes in antiestrogen-sensitive compared with antiestrogen-resistant (two tamoxifen resistant and two fulvestrant resistant) MCF-7 breast cancer cell lines. The branched-chain amino acid transaminase 1 (BCAT1), which catalyzes the first step in the breakdown of branched-chain amino acids, was among the most upregulated transcripts in antiestrogen-resistant cells. Elevated BCAT1 expression was confirmed in relapsed tamoxifen-resistant breast tumor specimens. High intratumoral BCAT1 levels were associated with a reduced relapse-free survival in adjuvant tamoxifen-treated patients and overall survival in unselected patients. On a tissue microarray (n=1421), BCAT1 expression was detectable in 58% of unselected primary breast carcinomas and linked to a higher Ki-67 proliferation index, as well as histological grade. Interestingly, BCAT1 was predominantly expressed in estrogen receptor-α-negative/human epidermal growth factor receptor-2-positive (ERα-negative/HER-2-positive) and triple-negative breast cancers in independent patient cohorts. The inverse relationship between BCAT1 and ERα was corroborated in various breast cancer cell lines and pharmacological long-term depletion of ERα induced BCAT1 expression in vitro. Mechanistically, BCAT1 indirectly controlled expression of the cell cycle inhibitor p27Kip1 thereby affecting pRB. Correspondingly, phenotypic analyses using a lentiviral-mediated BCAT1 short hairpin RNA knockdown revealed that BCAT1 sustains proliferation in addition to migration and invasion and that its overexpression enhanced the capacity of antiestrogen-sensitive cells to grow in the presence of antiestrogens. Importantly, silencing of BCAT1 in an orthotopic triple-negative xenograft model resulted in a massive reduction of tumor volume in vivo, supporting our findings that BCAT1 is necessary for the growth of hormone-independent breast tumors.

Radiotherapy with soft X-rays in Dupuytren's disease - successful, well-tolerated and satisfying.

BACKGROUND: Up to present no curative treatment is known for Dupuytren's disease (DD). Surgery remains the most common treatment but lack of long-term efficacy and complications limit this therapeutic option. OBJECTIVE: In a retrospective analysis, the results of radiotherapy with soft X-rays in the treatment of DD were evaluated. METHODS: A total of 206 patients (297 affected hands) with DD were included. Radiation therapy was carried out with soft X-rays. A structured questionnaire considering patient and disease characteristics and effects of radiotherapy was evaluated after a median follow-up time of 40 months. RESULTS: Ninety-three (45%) of the 206 treated patients were reported on a regression of symptoms after radiation. No further disease progression (including patients with regression) was present in 165 patients (80%). Satisfaction with the therapy was expressed with an average score of 7.9 points (visual analogue scale, 0 = not satisfied, 10 = extremely satisfied). Subjective therapeutic effects for 426 nodules and/or cords showed a reduction of 92 nodules and/or cords. CONCLUSION: In 206 DD patients further disease progression was stopped in most patients. Radiotherapy proved to be well-tolerated, successful and satisfying for the patients.

Patients and Methods of the PATH Biobank - A Resource for Breast Cancer Research.

Introduction: The foundation PATH (Patients' Tumour Bank of Hope) collects in a tumour bank samples of blood, tumour, and tumour-near normal tissue from breast cancer patients and supplements them systematically with health-care data. Material and Methods: For patients from the diagnosis years 2006-2009 quantitative data were evaluated with the help of mean values and standard deviations while for qualitative data absolute and relative incidences were assessed. Demographic and clinical features of women who used different numbers of information sources were tested for statistical significance by means of ANOVA and χ2 tests. The benchmark report of the WBC and two DMP reports were used to compare oncological care. Results: For research purposes tumour tissue samples are available for 59 % of the cases, normal tissue for 62 % and blood serum samples for 92 %. From 3573 women (diagnoses 2006-2009), a total of 2697 women (75.5 %) took part in follow-up. The characteristics of the follow-up patients did not relevantly differ from those of all the patients. The responsible physician was named as the most important source of information about the disease. Young women in particular consulted several sources and also used the internet to obtain information. Discussion: Compared with data on therapy from WBC and the DMP breast cancer in Bavaria or, respectively, North Rhineland reports, the PATH patients represent an only slightly selected sample. The PATH biobank is a (still) poorly used data and sample source, which is made available upon request and positive evaluation of the study protocol. Thus, it is possible to address current questions in a short time without having to undertake extensive recruiting procedures.

Bisphosphonates and their Role in Therapy for Breast Cancer - Results from the PATH Biobank.

Introduction: Bisphosphonates are well known above all for their use in the treatment of osteoporosis. They also play an important role as accompanying therapy for advanced tumour diseases with extensive spread into the skeletal system. Their adjuvant use in the treatment of breast cancer without bony metastases is currently a subject of controversial discussion. The objective of the present evaluation is to describe the use of bisphosphonates in the therapy for breast cancer. We will show how frequently bisphosphonates are used, which bisphosphonates are preferred and what specific features patients under bisphosphonate therapy exhibit. Methods and Materials: The pseudonymous data set from the biobank of the German PATH foundation was used for the evaluation. From the total collective, 2492 patients were selected after consideration of the inclusion and exclusion criteria. The selected patient collective was divided into two groups (with and without bisphosphonate therapy) and the two groups compared with one another with the help of descriptive statistics. Results: 17.5 % of the 2492 patients had prescriptions for a bisphosphonate as part of their therapy. The most frequently administered bisphosphonate was zoledronate. Pathological (induced by tumour therapy) osteoporosis was the most frequently stated indication among the bisphosphonate patients, followed by consumption starting prior to the breast cancer therapy and treatment of bony metastases. Patients under bisphosphonate and antihormonal therapy frequently received an aromatase inhibitor as the active principle in the antihormonal therapy whereas patients under antihormonal therapy but without bisphosphonates more frequently received tamoxifen as active principle. Ten of the 2492 patients reported receiving bisphosphonate therapy as prophylaxis for bony metastases without a documented and approved indication. Use of bisphosphonates in the course of the GAIN, ICE, SUCCESS or, respectively, NATAN trials was reported by 29 of the 2492 patients. Conclusions: In the PATH collective, bisphosphonates were employed above all for the treatment of (tumour therapy-induced) osteoporosis and bony metastases. Off-label use and participation in clinical trials played only a minor role in this patient collective. Against the background of the uncertain data status for the adjuvant use of bisphosphonates, the development (and use) of standardised, validated questionnaires to record the indications for and frequency of use of bisphosphonate therapy is recommended.