Umar Wazir

The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer

Lamin A/C (LMNA), lamin B1 (LMNB1) and lamin B receptor (LBR) have key roles in nuclear structural integrity and chromosomal stability. In this study, we have studied the relationships between the mRNA expressions of A-type lamins, LMNB1 and LBR and the clinicopathological parameters in human breast cancer. Samples of breast cancer tissues (n = 115) and associated non-cancerous tissue (ANCT; n = 30) were assessed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher levels of A-type lamins and LMNB1 mRNA expression were seen in ANCT. Higher lamin A/C expression was associated with the early clinical stage (TNM1 vs. TNM3 — 13 vs. 0.21; p = 0.0515), with better clinical outcomes (disease-free survival vs. mortality — 11 vs. 1; p = 0.0326), and with better overall (p = 0.004) and disease-free survival (p = 0.062). The expression of LMNB1 declined with worsening clinical outcome (disease-free vs. mortalities — 0.0011 vs. 0.000; p = 0.0177). LBR mRNA expression was directly associated with tumor grade (grade 1 vs. grade 3 — 0.00 vs. 0.00; p = 0.0479) and Nottingham Prognostic Index (NPI1 vs. NPI3 — 0.00 vs. 0.00; p = 0.0551). To the best of our knowledge, this is the first study to suggest such a role for A-type lamins, lamin B1 and LBR in human breast cancer, identifying an important area for further research.

Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer.

The mammalian target of rapamycin (mTOR) plays a key role in the regulation of cellular metabolism, growth and proliferation. It forms two multi-protein complexes known as complex 1 (mTORC1) and 2 (mTORC2). Raptor and Rictor are the core proteins for mTORC1 and mTORC2, respectively. This study examines the relationship between mTORC1, Rictor and Raptor mRNA expression and human breast cancer. Furthermore, the correlation between mTORC1 and hTERT was investigated. Breast cancer tissues (n=150) and normal tissues (n=31) were analysed using reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data. Higher mTOR expression was noted in breast cancer tissue (P=0.0018), higher grade tumours (grade 2 vs. 3, P=0.047), in ductal tumours (P=0.0014), and was associated with worse overall survival (P=0.01). Rictor expression was significantly higher in background breast tissues compared with tumours and was inversely related to the Nottingham Prognostic Index (NPI1 vs. 2, P=0.03) and tumour grade (grade 1 vs. 3, P=0.01) and was associated with better overall (P=0.037) and disease-free survival (P=0.048). The mRNA expression of Raptor was higher in tumours compared with normal tissues. Furthermore, the expression of Raptor was associated with a higher tumour grade (grade 1 vs. 3, P=0.027). A highly significant positive correlation between mTOR and hTERT (P<0.00001) was observed. These observations are consistent with the role of mTORC1 in the anti-apoptosis pathway and suggest that selective inhibitors of mTORC1 may be more efficacious in human breast cancer. Our findings support the hypothesis that mTORC1 is an important upregulator of telomerase in breast cancer.

Breast Lipofilling: A Review of Current Practice

Lipofilling is a reconstructive and aesthetic technique that has recently grown in popularity and is increasingly being used in breast surgery. Previous concerns had been raised regarding its safety when used for remodelling and reconstruction of the breast; however, these concerns have since been dismissed. Over the subsequent two decades, little evidence has been found to support these early theoretical concerns, and growing numbers of proponents of the procedure are confident in its safety. Many developments and refinements in the technique have taken place in recent years, and several studies have been published regarding the safety of lipofilling in the breast. We reviewed the current literature regarding the use of different lipofilling techniques as well as the current evidence regarding the oncological safety of the procedure in patients seeking aesthetic breast enhancement and in patients requiring reconstruction after treatment for breast cancer.

Pleomorphic lobular carcinoma in situ: Current evidence and a systemic review (Review)

Pleomorphic lobular carcinoma in situ (PLCIS) has only recently been identified as a distinct pathological entity within classic lobular carcinoma in situ (CLCIS). As such, there is currently no consensus among clinicians regarding the optimal treatment of this disease. The present study determined the risk of concomitant invasive disease and ductal carcinoma in situ (DCIS) if PLCIS is observed on core needle biopsy (CNB) and collated the evidence regarding the risk of recurrence in relation to surgical margins and adjuvant therapy. In addition, the pertinent literature available through MedLine, PubMed, the WHO Clinical Trials Registry Platform and Google Scholar using appropriate keywords was reviewed. The pooled results of studies in the literature demonstrated a concomitant presence of invasive disease of 40%, and 15% for DCIS. The studies that examined recurrence rates indicated that the risk is reduced with ample resection margins (>2 mm) and adjuvant radiotherapy. However, recent studies raise concerns regarding breast conservation when pursuing clear margins. No level 1 evidence from prospective studies, randomized controlled trials (RCTs), or meta-analyses based on such RCTs was identified. This is a clinical issue that warrants investigation in appropriately powered well designed prospective studies for a satisfactory resolution of all concerns.

Effects of the knockdown of death-associated protein 3 expression on cell adhesion, growth and migration in breast cancer cells

The death-associated protein 3 (DAP3) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP3 expression and clinicopathological parameters of human breast cancer. In the present study, we intended to determine the role of DAP3 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sub-lines of MCF7 and MDA-MB-231, and performed growth, adhesion, invasion assays and electric cell-substrate impedance sensing (ECIS) studies of post-wound migration of the cells. In addition, we studied the mRNA expression of caspase 8 and 9, death ligand signal enhancer (DELE), IFN-β promoter stimulator 1 (IPS1), cyclin D1 and p21 in the control and knockdown sub-lines. The knockdown sub-lines of MCF7 and MDA-MB-231 had significantly increased adhesion and decreased growth when compared to the controls. Furthermore, invasion and migration were significantly increased in the MDA-MB-231DAP3kd cells vs. the controls. The expression of caspase 9 and IPS1, known components of the apoptosis pathway, were significantly reduced in the MCF7DAP3kd cells (p=0.05 and p=0.003, respectively). We conclude that DAP3 silencing contributes to breast carcinogenesis by increasing cell adhesion, migration and invasion. It is possible that this may be due to the activity of focal adhesion kinase further downstream of the anoikis pathway. Further research in this direction would be beneficial in increasing our understanding of the mechanisms underlying human breast cancer.

The role of death-associated protein 3 in apoptosis, anoikis and human cancer

Death-associated protein 3 (DAP3) is a molecule with a significant role in the control of both apoptosis and anoikis. Apoptosis is the predominant type of programmed cell death (PCD) which may occur in response to irreparable damage to DNA, or in response to induction by inflammatory cells. Anoikis is subset of apoptosis which occurs in epithelial cells in response to detachment from the surrounding matrix. Both apoptosis and anoikis are of interest in the context of carcinogenesis. In this review, we shall discuss apoptosis and anoikis, and the recent literature regarding the role of DAP3 in both these pathways.

Emerging gene-based prognostic tools in early breast cancer: First steps to personalised medicine

Breast cancer remains a major cause of neoplastic disease in much of the developed world. The majority of cases are diagnosed with oestrogen receptor (ER)-positive and human epidermal growth factor receptor-2 negative invasive ductal carcinoma and are treated predominantly by surgery which includes sentinel node biopsy and adjuvant endocrine therapy ± adjuvant radiotherapy. It is believed that an indeterminate subset of the patient population is needlessly incurring chemotherapy related morbidity without attaining any increase in survival due to therapy. Furthermore in the era of extended adjuvant endocrine therapy it is important to identify those patients who can be safely treated with 5 years rather than 10 years of endocrine therapy thus optimising the benefit-risk balance. This perception has propelled the development of more personalised prognostic tools for newly diagnosed cases of ER-positive breast cancer. In this article, we shall review the evidence regarding the currently available gene assays for human breast cancer.

Towards optimal management of the axilla in the context of a positive sentinel node biopsy in early breast cancer.

The sentinel lymph node biopsy (SLNB) was initially pioneered for staging melanoma in 1994 and it has been subsequently validated by several trials, and has become the new standard of care for patients with clinically node negative invasive breast cancer. The focussed examination of fewer lymph nodes in addition to improvements in histopathological and molecular analysis has increased the rate at which micrometastases and isolated tumour cells are identified. In this article we review the literature regarding the optimal management of the axilla when the SLNB is positive for metastatic disease based on level 1 evidence derived from randomised clinical trials.

The Evolving Role of Pre-pectoral ADM-assisted Approach in Implant-based Immediate Breast Reconstruction Following Conservative Mastectomy: An Overview of the Literature and Description of Technique

Background/Aim: The recent development of acellular dermal matrix (ADM) devices has enhanced implant-based breast reconstruction surgery following conservative mastectomy for therapeutic and risk-reducing purposes leading to improved aesthetics. In the traditional sub-pectoral approach, coverage of the implant is provided by the pectoral muscles superiorly and the ADM inferiorly. The need to eliminate breast animation, reduce post-operative dysfunctional pain and the risk of capsular contracture, have stimulated surgeons to investigate the feasibility of placing the implant over the pectoralis major muscle with complete coverage with ADM thus inventing a novel pre-pectoral approach. Materials and Methods: We reviewed the literature regarding this evolving technique of muscle sparing ADM-assisted implant-based immediate breast reconstruction. Also, we describe our technique, and present pictures of the post-operative result. Results and Conclusion: The early reported results of the pre-pectoral breast reconstruction approach are encouraging and confirmed the potential benefits of eliminating breast animation and reducing postoperative pain. However, most of these studies had a small sample size (<100 patients) and were retrospective in nature with a limited follow-up duration and lack of data regarding the objective aesthetic assessment and oncological outcome. Nevertheless, suitable patients undergoing conservative mastectomy and implant-based reconstruction should be offered this option while further evaluation is being performed.

The Impact of EndoPredict Clinical Score on Chemotherapy Recommendations in Women with Invasive ER+/HER2−Breast Cancer Stratified as Having Moderate or Poor Prognosis by Nottingham Prognostic Index

Background: The Nottingham Prognostic Index (NPI) was developed using tumour pathological features to guide decisions regarding adjuvant therapy in breast cancer. Recent breakthroughs in molecular biology aided development of genomic assays such as EndoPredict, which have been shown to provide excellent prognostic information. The current study investigated the impact of EndoPredict Clinical (EPClin), a composite of clinicopathological data and EndoPredict score, on chemotherapy recommendations based on NPI. Patients and Methods: A total of 120 patients with oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer who were candidates for post-operative adjuvant chemotherapy at a single tertiary centre were included. Both NPI and EPClin were applied to all patients. NPI differentiated patients into groups with excellent/good prognosis (N=41; NPI≤3.4) or moderate/poor prognosis (N=79; NPI >3.4). The latter were considered for adjuvant chemotherapy. Results: There was discordance in results of 31% of cases; 35% of the patients/candidates for adjuvant chemotherapy according to NPI were reclassified as being at low risk of recurrence by EPClin. Conclusion: Genomic profiling using EPClin reduces the potential need for adjuvant chemotherapy in women with ER+/HER2− breast cancer who are candidates for chemotherapy according to the NPI.