Ramsey I. Cutress

BAG-1: a multifunctional regulator of cell growth and survival

BAG-1 is multifunctional protein which interacts with a wide range of cellular targets to regulate growth control pathways important for normal and malignant cells, including apoptosis, signaling, proliferation, transcription and cell motility. Of particular relevance to tumour cells, BAG-1 interacts with the anti-apoptotic BCL-2 protein, various nuclear hormone receptors and the 70 kDa heat shock proteins, Hsc70 and Hsp70. Interaction with chaperones may account for many of the pleiotropic effects associated with BAG-1 overexpression. Recent studies have shown that BAG-1 expression is frequently altered in malignant cells, and BAG-1 expression may have clinical value as a prognostic/predictive marker. This review summarises current understanding of molecular mechanisms of BAG-1 expression and function.

Intraoperative assessment of sentinel lymph nodes in breast cancer.

Sentinel lymph node biopsy (SLNB) reduces the morbidity of axillary clearance and is the standard of care for patients with clinically node‐negative breast cancer. The ability to analyse the sentinel node during surgery enables a decision to be made whether to proceed to full axillary clearance during primary surgery, thus avoiding a second procedure in node‐positive patients.

Prospective Observational Study of Breast Cancer Treatment Outcomes for UK Women Aged 18–40 Years at Diagnosis: The POSH Study

BACKGROUND Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. METHODS Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. RESULTS Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. CONCLUSIONS These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription

BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets including heat-shock proteins and some nuclear hormone receptors. BAG-1 exists as three major isoforms, BAG-1L, BAG-1M and BAG-1S. BAG-1L contains a nuclear localization signal, which is not present in the other isoforms, and is predominantly localized in the cell nucleus. Here we have investigated the effects of BAG-1 on function of the oestrogen receptor (ER), a key growth control molecule and target for hormonal therapy in breast cancer. We demonstrate that BAG-1L, but not BAG-1S or BAG-1M, increased oestrogen-dependent transcription in breast cancer cells. BAG-1L interacted with and stimulated the activity of both ER α and β. Although BAG-1L and ERs colocalize to the nucleus, fusing BAG-1S to an heterologous nuclear localization sequence was not sufficient to stimulate transcription. Consistent with an important effect on receptor function, nuclear BAG-1 expression in breast cancers was associated with expression of the progesterone receptor, a transcriptional target of ERα, and was associated with improved survival in patients treated with hormonal therapy. These data suggest that BAG-1L is an important determinant of ER function in vitro and in human breast cancer.

BAG-1 expression in human breast cancer: interrelationship between BAG-1 RNA, protein, HSC70 expression and clinico-pathological data

BAG‐1 (BCL‐2 athanogene‐1), a multifunctional protein which associates with steroid hormone receptors (including the oestrogen receptor) and the anti‐apoptotic BCL‐2 protein, regulates steroid hormone‐dependent transcription and apoptosis. Direct interaction with 70 kD heat‐shock proteins, HSC70 and HSP70, may mediate the diverse functions of BAG‐1. Immunohistochemistry was used to examine the expression of BAG‐1 and HSC70 in 160 cases of invasive breast cancer. BAG‐1 was expressed in 92% of cases; most tumours exhibited cytoplasmic BAG‐1, while a smaller proportion also had nuclear immunostaining. There was a significant inverse correlation between histological grade and nuclear BAG‐1 expression, with higher‐grade tumours tending to have reduced nuclear BAG‐1 expression, but there was no association with cytoplasmic BAG‐1. There was also no significant correlation between nuclear or cytoplasmic BAG‐1 expression and oestrogen receptor positivity. Since BAG‐1 may be influenced by hormonal background, the relationship between grade and oestrogen receptor was examined separately in pre‐menopausal and post‐menopausal women. The statistically significant correlation between nuclear BAG‐1 expression and low tumour grade was strong in pre‐menopausal, but not apparent in post‐menopausal women. A statistically significant correlation was observed between cytoplasmic, but not nuclear, BAG‐1 expression and oestrogen receptor status in pre‐menopausal, but not post‐menopausal, women. There was no correlation between BAG‐1 protein expression and RNA, suggesting that important post‐transcriptional mechanisms control BAG‐1 expression in vivo. HSC70 was also detected in the majority (97%) of cases, although expression was not correlated with BAG‐1 levels, oestrogen receptor status or tumour grade. Overall survival in cases with high levels of nuclear BAG‐1 expression was improved, though not significantly. These results are consistent with the hypothesis that BAG‐1 plays an important but variable role in breast cancers developing in pre‐menopausal and post‐menopausal women. Copyright

BAG-1 expression and function in human cancer

BAG-1 is a multifunctional protein that interacts with a wide range of target molecules to regulate apoptosis, proliferation, transcription, metastasis and motility. Interaction with chaperone molecules may mediate many of the effects of BAG-1. The pathways regulated by BAG-1 play key roles in the development and progression of cancer and determining response to therapy, and there has been considerable interest in determining the clinical significance of BAG-1 expression in malignant cells. There is an emerging picture that BAG-1 expression is frequently altered in a range of human cancers relative to normal cells and a recent report suggests the exciting possibility that BAG-1 expression may have clinical utility as a prognostic marker in early breast cancer. However, other studies of BAG-1 expression in breast cancer and other cancer types have yielded differing results. It is important to view these findings in the context of current knowledge of BAG-1 expression and function. This review summarises recent progress in understanding the clinical significance of BAG-1 expression in cancer in light of our understanding of BAG-1 function.

Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance.

Background information. CtBPs [C‐terminal (of E1A) binding protein] have roles in the nucleus as transcriptional co‐repressors, and in the cytoplasm in the maintenance of vesicular membranes. CtBPs are expressed from two genes, CTBP1 and CTBP2, mRNA products of which are alternatively spliced at their 5′‐ends to generate distinct protein isoforms. Extensive molecular and cellular analyses have identified CtBPs as regulators of pathways critical for tumour initiation, progression and response to therapy. However, little is known of the expression or regulation of CtBP isoforms in human cancer, nor of the relative contributions of CTBP1 and CTBP2 to the tumour cell phenotype.

Obesity in breast cancer--what is the risk factor?

Environmental factors influence breast cancer incidence and progression. High body mass index (BMI) is associated with increased risk of post-menopausal breast cancer and with poorer outcome in those with a history of breast cancer. High BMI is generally interpreted as excess adiposity (overweight or obesity) and the World Cancer Research Fund judged that the associations between BMI and incidence of breast cancer were due to body fatness. Although BMI is the most common measure used to characterise body composition, it cannot distinguish lean mass from fat mass, or characterise body fat distribution, and so individuals with the same BMI can have different body composition. In particular, the relation between BMI and lean or fat mass may differ between people with or without disease. The question therefore arises as to what aspect or aspects of body composition are causally linked to the poorer outcome of breast cancer patients with high BMI. This question is not addressed in the literature. Most studies have used BMI, without discussion of its shortcomings as a marker of body composition, leading to potentially important misinterpretation. In this article we review the different measurements used to characterise body composition in the literature, and how they relate to breast cancer risk and prognosis. Further research is required to better characterise the relation of body composition to breast cancer.

Patient satisfaction following nipple-areolar complex reconstruction and tattooing

BACKGROUND Nipple-areolar complex (NAC) reconstruction and tattooing complete and compliment reconstruction of the breast mound. Patient satisfaction with NAC reconstruction and tattoo, independent from breast mound reconstruction is evaluated in this study. METHODS Patients who underwent nipple tattooing between January 2001 and June 2008 were sent a postal questionnaire retrospectively. Questions included those regarding reconstruction type, patient satisfaction with NAC reconstruction and tattoo outcome, and complications. RESULTS 110 patients with completed questionnaires were included from the 172 patients who were invited. Median follow up time was 38.5 months (1-86). Eighty eight percent reported overall satisfaction with their NAC reconstruction. Seventy percent of patients were satisfied with their nipple tattoos. All procedures were done in a day case setting and eighty-nine patients reported no postoperative complications. The commonest causes for disappointment were lack of projection of the NAC reconstruction and fading of tattoos. Ninety-six percent of women stated that NAC reconstruction and tattooing were important to them, and 93% of the patients would undergo the procedures again. CONCLUSION We believe that NAC reconstruction is an important and integral part of breast reconstruction. This study should inform surgeons and patients regarding outcome, possible complications and the potential need and timing of further tattooing.

Observational and cost analysis of the implementation of breast cancer sentinel node intraoperative molecular diagnosis

Background Accurate intraoperative sentinel lymph node (SLN) assessment enables axillary clearance to be completed immediately in node-positive breast cancer patients. This article reports a study of the introduction of intraoperative molecular SLN analysis in routine clinical practice in the Portsmouth Breast Care Centre. Design There was prospective analysis of 254 consecutive patients who underwent SLN biopsy in a single centre. Nodes were sectioned at 2 mm intervals and alternate slices were analysed using a CE-marked assay for mammaglobin (MG) and cytokeratin 19 (CK19). Remaining slices of node were sent for histological analysis, which included CK19 immunohistochemistry. While the assay was being carried out, the surgeon performed the breast tumour resection. The cost per patient was estimated retrospectively and the cost effects on the hospital and primary care trust for a typical service were also estimated. Results A total of 491 SLNs from 254 patients were evaluated. The intraoperative assay showed positivity of SLNs for metastatic cells in 78 patients. There was 100% detection of macrometastases within sentinel nodes analysed by GeneSearch. Overall concordance between histological status, including micrometastases and GeneSearch analysis, was 95% (sensitivity 96%, specificity 95%). The cost per procedure was increased for wide local excision with SLN biopsy and intraoperative assessment compared with other models, but fewer procedures were carried out. Conclusion Intraoperative assessment of SLNs in breast cancer using a molecular assay is a safe, acceptable and accurate technique that allows a reduction in the frequency of delayed axillary clearance surgery. Take-up of this method may be hampered by perverse incentives operating within healthcare funding.