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Background and Objective: Membrane solute carrier transporters play an important role in the transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess the prognostic relevance of gene expression and genetic variability of selected solute carrier transporters in breast cancer., Methods: Gene expression was determined by quantitative real-time polymerase chain reaction. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in DNA extracted from the blood of patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology. Common variants (minor allele frequency ≥ 5%) with in silico-predicted functional relevance were further analyzed in a large cohort of patients with breast cancer (n = 815) and their prognostic and predictive potential was estimated (validation phase)., Results: A gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in the prognosis of patients with breast cancer. In total, 135 genetic variants (20 novel) were identified in both genes in the exploratory phase. Of these variants, 130 were non-coding, three missense, and two synonymous. One common variant in SLCO1A2 and four variants in SLC46A1 were predicted to be pathogenic by in silico programs and subsequently validated. A SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients., Conclusions: This study revealed the prognostic value of a SLC46A1 haplotype block for breast cancer that should be further studied.

Background/aims: MiRNA-301a-3p is an oncogenic miRNA whose expression is associated with tumor development, metastases and overall poor prognosis. Estrogen receptor α (ERα) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERα is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERα in breast cancer patients indicates invasiveness and poor prognosis. In this study, we focus on the regulation of ERα by miR-301a and its role in transition from estrogen-dependent to estrogen-independent breast cancer., Methods: Expression of miR-301a-3p was measured by qRT-PCR in tumor tissue samples from 111 patients with primary breast carcinoma and in mammospheres representing in vitro model of cancer stem-like cells. Dual reporter luciferase assay and complementary experiments were performed to validate ESR1 as a direct target of miR-301a-3p. The effect of miR-301a-3p on estrogen signaling was evaluated on the level of gene and protein expression and growth response to estrogens. Finally, the effect of miR-301a-3p expression on tumor growth was studied in nude mice., Results: We identified ESR1 as a direct target of miR-301a-3p. Ectopic miR-301a-3p causes a decrease in ESR1 mRNA and protein level and modulates the expression of ERα target genes in ERα positive breast cancer cells. Consistently, miR-301a-3p causes a decrease in sensitivity of MCF7 cells to 17β-estradiol and inhibits the growth of estrogen dependent tumor in nude mice. Yet, the mice tumors have significantly increased expression of genes related to cancer stem-like cells and epithelial to mesenchymal transition suggesting enrichment of the population of cells with more invasive properties, in line with our observation that miR-301a-3p expression is highly increased in mammospheres which show a decrease in estrogenic signaling. Importantly, miR-301a-3P level is also increased in primary breast cancer samples exhibiting an ER/PR negative phenotype., Conclusion: Our results confirm ESR1 as a direct target of miR-301a-3p and suggest that miR-301a-3p likely contributes to development of estrogen independence, which leads to a more invasive phenotype of breast cancer., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Objective: This study investigated whether gene expression levels of key modulators of the oxysterol signalling pathway modify the prognosis of patients with oestrogen receptor-positive (ER+) breast carcinomas via interaction with endocrine therapy., Context: The prognosis of patients with ER+ breast carcinoma depends on several factors. Previous studies have suggested that some oxygenated forms of cholesterol (oxysterols) bind to oestrogen receptor and anti-oestrogen binding site which may deregulate cholesterol homoeostasis and influence effect of therapy., Design: The expression levels of 70 oxysterol pathway genes were evaluated in a test set of breast carcinomas differing in ER expression. The genes differentially expressed in ER+ tumours were assessed in a comprehensive set of ER+ tumours to evaluate their clinical significance., Patients: A total of 193 primary patients with breast carcinoma were included., Measurements: The transcript levels were determined by quantitative real-time polymerase chain reaction., Results: The expression levels of 23 genes were found to be specifically dysregulated in ER+ tumours compared to ER- tumours of the test set. The expression levels of ABCG2, CYP7B1, CYP24A1, CYP39A1 and CH25H genes were found to be strongly associated with disease stage; however, none of the gene expression levels were associated with disease-free survival in patients treated with endocrine therapy., Conclusions: The expression of a number of oxysterol pathway genes is significantly modulated by ER expression and associated with the clinical stage of patients. However, the expression of oxysterol pathway genes was not found to modify the prognosis of ER+ patients with breast carcinoma treated with endocrine therapy., (© 2017 John Wiley & Sons Ltd.)

Background: Apoptosis plays a critical role in cancer cell survival and tumor development. We provide a hypothesis-generating screen for further research by exploring the expression profile and genetic variability of caspases (2, 3, 7, 8, 9, and 10) in breast carcinoma patients. This study addressed isoform-specific caspase transcript expression and genetic variability in regulatory sequences of caspases 2 and 9., Methods: Gene expression profiling was performed by quantitative real-time PCR in tumor and paired non-malignant tissues of two independent groups of patients. Genetic variability was determined by high resolution melting, allelic discrimination, and sequencing analysis in tumor and peripheral blood lymphocyte DNA of the patients., Results: CASP3 A+B and S isoforms were over-expressed in tumors of both patient groups. The CASP9 transcript was down-regulated in tumors of both groups of patients and significantly associated with expression of hormonal receptors and with the presence of rs4645978-rs2020903-rs4646034 haplotype in the CASP9 gene. Patients with a low intratumoral CASP9A/B isoform expression ratio (predicted to shift equilibrium towards anti-apoptotic isoform) subsequently treated with adjuvant chemotherapy had a significantly shorter disease-free survival than those with the high ratio (p=0.04). Inheritance of CC genotype of rs2020903 in CASP9 was associated with progesterone receptor expression in tumors (p=0.003)., Conclusions: Genetic variability in CASP9 and expression of its splicing variants present targets for further study.

Background: The management of internal mammary nodes (IMNs) during multidisciplinary treatment of breast cancer has been debated for the last four decades without unequivocal conclusion., Patients and Methods: We retrospectively reviewed patients with breast cancer who underwent sentinel lymph node biopsy at our center from 2008 until 2012. IMN drainage was assessed as a potential risk factor for local and distant disease recurrence., Results: We identified 712 patients, with incidence of drainage to IMNs of 18.4%. No detrimental effect of the pattern of drainage to IMNs was found after a median follow-up of 58 months. A similar outcome was observed when drainage to IMNs was evaluated as a risk factor for patient survival. The potential risk factors for drainage to IMNs during sentinel lymph node biopsy were younger age (p=0.002) and tumor location in lower-outer, lower-inner, and upper-inner versus upper-outer quadrant (p<0.0001)., Conclusion: The drainage to IMNs is unlikely to have a detrimental effect on patient outcome., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Microtubules are vitally important for eukaryotic cell division. Therefore, we evaluated the relevance of mitotic kinesin KIF14, protein-regulating cytokinesis 1 (PRC1), and citron kinase (CIT) for the prognosis of breast carcinoma patients. Transcript levels were assessed by quantitative real-time PCR in tissues from two independent groups of breast carcinoma patients and compared with clinical data. Tissue PRC1 protein levels were estimated using immunoblotting, and the PRC1 tagged haplotype was analyzed in genomic DNA. A functional study was performed in MDA-MB-231 cells in vitro. KIF14, PRC1, and CIT transcripts were overexpressed in tumors compared with control tissues. Tumors without expression of hormonal receptors or high-grade tumors expressed significantly higher KIF14 and PRC1 levels than hormonally-positive or low-grade tumors. Patients with high intra-tumoral PRC1 levels had significantly worse disease-free survival than patients with low levels. PRC1 rs10520699 and rs11852999 polymorphisms were associated with PRC1 transcript levels, but not with patientś survival. Paclitaxel-induced PRC1 expression, but PRC1 knockdown did not modify the paclitaxel cytotoxicity in vitro. PRC1 overexpression predicts poor disease-free survival of patients with breast carcinomas. Genetic variability of PRC1 and the protein interaction with paclitaxel cytotoxicity do not explain this association., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Breast cancer is, now often diagnosed in patients older than 70 years due to longer life expectancy. The usual treatment is mastectomy to obviate radiotherapy or breast-conserving surgery followed by radiotherapy. The aim of this study was to investigate the need for adjuvant radiotherapy in older patients and the consequences of omitting radiotherapy following conservative surgery., Methods: An extensive database search was made of patients who had been treated for breast cancer at the Department of Oncology, University Hospital Olomouc and the Atlas Hospital in Zlin (2004-2008). We identified 738 patients of whom 190 patients (25.7%) were older than 70 years of age. These were followed up for progression-free and overall survival. The cause of death was checked for breast cancer relapse., Results: In total only 9 patients undergoing breast saving surgery were ultimately identified. No patient had confirmed local recurrence during the follow up period: Two patients have died due to distant metastasis without local relapse and one patient has died for reasons other than breast cancer., Conclusion: Omitting radiotherapy after breast saving surgery provides an opportunity for women to undergo breast saving surgery and avoid 7 weeks of radiotherapy. This could significantly improve patient quality of life. In our of many years experience and from published randomized data, this procedure is safe for a select group of patients 70 years of age and older.

Introduction: Breast cancer treatment currently represents one of the biggest challenges in clinical oncology. The gold standard for axillary lymph node management is to perform sentinel node biopsy to avoid axillary dissection and its sequelae. The detection of radiocolloid flow outside the axillary nodes is a diagnostic and therapeutic challenge., Methods: A database search at the Department of Oncology of Palacky University, Olomouc, Czech Republic, identified 127 patients who underwent breast cancer resection with a sentinel node procedure and had radiocolloid flow into the internal mammary nodes. Sentinel node lymphoscintigraphy was performed after intraparenchymal injection. Clinical and pathological data were collected to identify possible risk factors., Results: Ten clinical and pathological parameters including age, tumor histology, axillary lymph node status, estrogen receptor expression, progesterone receptor expression, tumor grade, Ki-67 expression, Her-2 status, tumor size and tumor location were analyzed with regard to internal mammary node drainage. A cohort of 127 patients with detected drainage into the internal mammary nodes was compared with 135 patients without such drainage. Six significant risk factors, including age <50 years ( P <0.0313), tumor location in central and inner quadrants (P <0.012), larger tumor size (P <0.017), positive Her-2 status (P <0.025), progesterone receptor expression (P <10-4) and axillary lymph node involvement (P <0.01) were found to predict radiocolloid flow into the internal mammary nodes., Conclusion: Six parameters (patient age, tumor location, hormone receptor status, tumor size, Her-2 status and axillary lymph node status) should be considered in the management of breast cancer patients and help in the selection of patients for locoregional procedures encompassing the internal mammary nodes.

Introduction: Breast conserving surgery combined with sentinel node biopsy represents currently the gold standard of treatment for early breast cancer. Although breast conserving surgery has been a widely accepted method for many years, there remain some highly controversial unresolved issues. The present analysis focused on the resection margin as one of the key factors for local control of the disease., Methods: Patient disease free survival and overall survival were collected from patients undergoing breast conserving surgery from 2004 to 2009 at the Department of Surgery Atlas hospital Zlin, Czech Republic. All patients with resection margin less then 5 mm were re-resected to achieve this clear resection margin of 5mm or more. Disease free survival (more specifically local relapse free survival, metastasis free survival and regional free survival) and overall survival were assessed., Results: The data on 330 patients were analyzed and 286/330 cases had complete follow-up. After a median follow-up of 70 months, 7 patients with isolated local relapse were identified (2.44%), 13 patients with distant metastasis without local relapse (4.54%) and 2 patients with relapse in the axilla without local relapse in the breast (0.7%)., Conclusion: The final decision about the extent of resection margin remains controversial but based on the data on local control presented here it seems reasonable to increase the criteria for a clear resection margin to 5 mm.

Background: Internal mammary nodes visualized during sentinel node biopsy for breast cancer, remain an unresolved management issue. Further, both internal mammary node (IMN) radiotherapy and biopsy have attendant risks and hence should be used with caution. The purpose of this review is to highlight the available data and evidence., Methods and Results: A PubMed database from 1960 to 2012 using key words: internal mammary nodes, breast cancer radiotherapy planning, adjuvant radiotherapy, sentinel node biopsy in breast cancer and selected publications on the significance of internal mammary nodes in breast cancer treatment, published data and approaches used. We found 14513 relevant papers and we selected 30 that clearly investigated the management of internal mammary nodes during sentinel node search. We focused on the incidence of IMN metastasis (6 papers), risk factors associated with IMN drainage (9 reports), management of IMN and the impact on disease free and overall patient survival (15 papers)., Conclusions: The evidence for breast cancer axillary nodes management is good but the data for other draining nodes such as internal mammary nodes are far less conclusive and further research is needed.