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Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10−5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10−6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10−13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0–12.6 and PR-positive OR = 1.7, 95% CI: 1.3–2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4–4.4; P = 4.4 × 10−14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18–0.35; P = 2.3 × 10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 21(1); 134–47. ©2011 AACR.

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After lytic polysaccharide monooxygenase (LPMO) treatment, colloidally stable and thin cellulose nanofibrils (CNFs) of a uniform width are produced from kraft pulp fibres, which has a higher hemicellulose content than dissolving pulp fibres.

Temperature is a fundamental parameter for all forms of lives. Natural evolution has resulted in organisms which have excellent thermoregulation capabilities in extreme climates. Bioinspired materials that mimic biological solution for thermoregulation have proven promising for passive radiative cooling. However, scalable production of artificial photonic radiators with complex structures, outstanding properties, high throughput, and low cost is still challenging. Herein, we design and demonstrate biologically inspired photonic materials for passive radiative cooling, after discovery of longicorn beetles’ excellent thermoregulatory function with their dual-scale fluffs. The natural fluffs exhibit a finely structured triangular cross-section with two thermoregulatory effects which effectively reflects sunlight and emits thermal radiation, thereby decreasing the beetles’ body temperature. Inspired by the finding, a photonic film consisting of a micropyramid-arrayed polymer matrix with random ceramic particles is fabricated with high throughput. The film reflects ∼95% of solar irradiance and exhibits an infrared emissivity >0.96. The effective cooling power is found to be ∼90.8 W⋅m(−2) and a temperature decrease of up to 5.1 °C is recorded under direct sunlight. Additionally, the film exhibits hydrophobicity, superior flexibility, and strong mechanical strength, which is promising for thermal management in various electronic devices and wearable products. Our work paves the way for designing and fabrication of high-performance thermal regulation materials.

Functionalized gold nanostructures with efficient, broadband absorption properties are of interest for a variety of biomedical applications. In this study, we report a plasmon-enhanced functionalization methodology that results in selective surface conjugation of a fluorescent probe via two-photon excitation under visible-wavelength laser irradiation. The fluorescent probe was designed to incorporate a thiolated 4-piperidinyl-1,8-naphthalimide (SNaph) entity, carrying a photolabile 6-nitroveratryl (NV) protecting group, straightforwardly synthesized in a few steps in good yield. Efficient plasmon-enhanced photodeprotection of the NV-group, followed by thiol-gold bond formation on gold nanoisland substrates was recorded upon exposure to 650 nm laser light, supported by confocal laser scanning microscopy (CLSM). Photolysis of the labile NV-group, thereby efficiently exposing the free mercapto group of the thiolated 1,8-naphthalimide, was recorded upon UV-irradiation at 350 nm, whereas no cleavage occurred at 650 nm. No conjugation occurred on featureless, gold-plated flat substrates under the same conditions. Surface plasmon-enhanced two-photon excitation at plasmonic hotspots in the absorber layer thus resulted in selective and efficient conjugation of the fluorescent probe to the structured surfaces. The resulting laser-assisted approach introduces the advantage of accomplishing selective molecular functionalization at plasmonic hotspots, owing to the combined, simultaneous effects of long-wavelength deprotection and spontaneous conjugation.

We report design and simulation results of a high-efficiency long-wavelength cut-off filter realized by stepped impedance resonators. Moreover, numerical results confirm by modulating the length of resonator, cut-off wavelength can be easily tuned.

Refractive index (RI) determination for delignified wood templates is vital for transparent wood composite fabrication. Reported RIs in the literature are based on either single plant fibers or wood powder, measured by the immersion liquid method (ILM) combined with mathematical fitting. However, wood structure complexity and the physical background of the fitting were not considered. In this work, RIs of delignified wood templates were measured by the ILM combined with a light transmission model developed from the Fresnel reflection/refraction theory for composite materials. The RIs of delignified balsa wood are 1.536 ± 0.006 and 1.525 ± 0.008 at the wavelength of 589 nm for light propagating perpendicular and parallel to the wood fiber direction, respectively. For delignified birch wood, corresponding values are 1.537 ± 0.005 and 1.529 ± 0.006, respectively. The RI data for delignified wood scaffolds are important for tailoring optical properties of transparent wood biocomposites, and also vital in optical properties investigations by theoretical modelling of complex light propagation in transparent wood and related composites. The developed light transmission model in combination with the immersion liquid method can be used to determine the RI of complex porous or layered solid materials and composites.

Metamaterials with spectrally selective absorptance operating in the mid-infrared range have attracted much interest in numerous applications. However, it remains a challenge to economically fabricate scalable meta-absorbers with tailorable absorptance bands. This work demonstrates a conceptually simple and low-cost yet effective design strategy to achieve spectrally selective absorption with tailorable band positions at MIR by colloidal lithography. The strategy ingeniously uses residual diameter fluctuations of circular resonators etched through monodisperse colloidal particles for achieving superposition of multiple magnetic resonances and thereby a more than doubled absorption band, which is neglected in previous works. The proposed meta-absorber features densely packed thick aluminum resonators with a rather narrow diameter distribution and enhanced capacitive coupling among them. Moreover, the tailorability of the absorption band can be achieved by a parameterized variation in the fabrication process. As a proof of concept, infrared stealth and radiative cooling are demonstrated based on our meta-absorbers. The design and fabrication strategy create versatile metamaterials for advanced radiative thermal engineering.

We propose an on-chip reconfigurable mode-order converter based on subwavelength symmetric multimode Y-junctions, assisted by phase shifters. The data information carried among four different mode channels can be arbitrarily converted or remain the same.

Adiabatic multimode Y-junctions are extensively used for the design of multimode silicon photonics devices due to their straightforward principle in achieving mode splitting and manipulation. However, experimentally, the limited feature size achievable by lithography can greatly deteriorate the adiabatic branching property and result in large excess loss and crosstalk. Here, we propose a branch structure consisting of a circular-hole-based chirped subwavelength slot. By optimizing the holes’ radii and positions under our fabrication constraint, we designed and experimentally demonstrated both symmetric and asymmetric approximately adiabatic four-mode Y-junctions with excellent performance close to ideal Y-junctions over a broad wavelength span. Such junctions are compact, CMOS-compatible, exhibit a relatively large fabrication tolerance, and could be extended for more modes; hence they can be potentially deployed for mode-division multiplexing silicon-photonic systems.

Inverse-designed digital nanophotonic devices have been widely and successfully used due to their simple brute-force design methods, compact footprint, flexibly-designed functions and high performance in various applications. Unfortunately, the number of 3D FDTD simulations in brute-force methods will increase exponentially with the "pixel" number in a digital pattern, which may drastically limit the inverse design capability of digital nanophotonic devices. In this work, we propose and demonstrate a modified adjoint method for efficient inverse design of compact digital nanophotonic power dividers with arbitrary power ratios.

Nacre-inspired clay nanocomposites have excellent mechanical properties, combined with optical transmittance, gas barrier properties, and fire retardancy, but the mechanical properties are still be ...

In order to stabilize the extinction cross section measurement of a single nanoparticle, we propose to analyze the blurriness parameter of aperture edge images in real time, which provides a feedback to lock the sample position. Unlike the conventional spatial modulation spectroscopy (SMS) technique, a probe beam experiences both the spatial modulation by a piezo stage and the temporal modulation by a chopper. We experimentally demonstrate that the measurement uncertainty is one order magnitude less than that in the previous report. The proposed method can be readily implemented in conventional SMS systems and can help to achieve high stability for sensing based on light extinction by a single nanoparticle, which alleviate the impact from laboratory environment and increase the experimental sensitivity.

A novel power-efficient reconfigurable mode converter is proposed and experimentally demonstrated based on cross-connected symmetric Y-junctions assisted by thermo-optic phase shifters on a silicon-on-insulator platform. Instead of using conventional Y-junctions, subwavelength symmetric Y-junctions are utilized to enhance the mode splitting ability. The reconfigurable functionality can be realized by controlling the induced phase differences. Benefited from the cross-connected scheme, the number of heating electrodes can be effectively reduced, while the performance of the device is maintained. With only one-step etching, our fabricated device shows the average insertion losses and cross talks are less than 2.45 and − 16.6 dB , respectively, measured with conversions between two arbitrary compositions of the first four TE modes over an observable 60 nm bandwidth. The converter is switchable and CMOS-compatible, and could be extended for more modes; hence, it can be potentially deployed for advanced and flexible mode multiplexing optical networks-on-chip.

Polymer materials offer process compatibility, design flexibility, and low cost technology as a multi-functional platform for optical communication and photonics applications. Design and thermal reflowing technology of low loss polymer waveguides, as well as demonstration of transparent wood laser are presented in this paper.

Transparent wood (TW) is a biocomposite material with hierarchical structure, which exhibits high optical transmittance and anisotropic light scattering. Here, the relation between anisotropic scattering and the internal structure of transparent wood is experimentally studied and the dependence of scattering anisotropy on material thickness, which characterizes the fraction of ballistic photons in the propagating light, is shown. The limitations of the conven-tional haze, as it is implemented to isotropic materials, are discussed, and a modified characteristic parameter of light scattering—the degree of aniso-tropic scattering is defined. This parameter together with the transport mean free path value is more practical and convenient for characterization of the material scattering properties. It is believed that the generic routine described in this paper can be applied for scattering characterization and comparison of other TW materials of either different thickness, optical quality or based on various wood species. QC 20181126

Estrogen receptor (ER) α has been studied extensively in familial breast cancers but there are limited data on ERβ and its isoforms. This is an important issue since many BRCA1-associated tumours are "triple negative" and are resistant to conventional and targeted therapies. We performed an immunohistochemical study of pan-ERβ, ERβ1 and ERβ2 in a cohort of 123 familial breast carcinomas (35 BRCA1, 33 BRCA2 and 55 BRCAX) using a cut-off for positivity at 20% (Shaaban et al. in Clin Cancer Res 14:5228-5235, 2008). BRCA1 cancers were more likely to be nuclear ERα negative and nuclear pan-ERβ positive (21/32, 66%) when compared with BRCA2 (2/29, 7%) and BRCAX cancers (11/49, 22%) (both P0.001). For survival analysis, expression was also stratified using cut-offs defined by Bates et al. (Breast Cancer Res Treat 111:453-459, 2008) (score out of 7). Cytoplasmic ERβ2 expression correlated with shorter overall survival at 15 years regardless of cut-off used (both P0.046) At a cut-off score of 6 out of 7, cytoplasmic ERβ2 expression correlated with a poorer response to chemotherapy in both univariate (P = 0.011) and multivariate analyses including grade, lymph node status and chemotherapy as an interaction variable (P = 0.045, Hazard ratio 1.22, 95% CI 1.004-9.87). A similar trend was seen in a univariate analysis with a cut-off of 20% although this did not reach statistical significance (P = 0.057). Expression of nuclear ERβ1 was associated with a favourable response to endocrine therapy at 15 years regardless of cut-offs employed (both P0.025). However, this did not reach statistical significance in a multivariate analysis (P0.05). Since a significant proportion of ERα negative familial breast carcinomas are positive for nuclear ERβ1 and cytoplasmic ERβ2, the different ERβ isoforms and their intracellular location may need to be assessed, to identify patients that may benefit from hormonal and chemotherapy.

Background: There are limited data regarding the hypoxia pathway in familial breast cancers. We therefore performed a study of hypoxic factors in BRCA1, BRCA2 and BRCAX breast cancers. Methods: Immunoperoxidase staining for HIF-1α, PHD1, PHD2, PHD3, VEGF and FIH was carried out in 125 (38 BRCA1, 33 BRCA2 and 54 BRCAX) breast carcinomas. These were correlated with clinicopathological parameters and the intrinsic breast cancer phenotypes. Results: BRCA1 tumours correlated with positivity for HIF-1α (P=0.008) and negativity for PHD3 (P=0.037). HIF-1α positivity (P=0.001), PHD3 negativity (P=0.037) and nuclear FIH negativity (P=0.011) was associated with basal phenotype. HIF-1α expression correlated with high tumour grade (P=0.009), negative oestrogen receptor (ER) status (P=0.001) and the absence of lymph node metastasis (P=0.028). Nuclear FIH expression and PHD3 correlated with positive ER expression (P=0.024 and P=0.035, respectively). BRCA1 cancers with positive HIF-1α or cytoplasmic FIH had a significantly shorter relapse-free survival (P=0.007 and P=0.049, respectively). Conclusions: The aggressive nature of BRCA1 and basal-type tumours may be partly explained by an enhanced hypoxic drive and hypoxia driven ER degradation because of suppressed PHD and aberrantly located FIH expression. This may have important implications, as these tumours may respond to compounds directed against HIF-1α or its downstream targets.

Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .

Background:The role of FOXP1 in sporadic breast cancers has been widely studied but its role in familial breast cancers is yet unexplored.Aims:To investigate FOXP1 expression in different molecular subtypes of familial breast cancers and to correlate its expression with clinicopathological parameters, oestrogen receptors (ER) and survival.Methods:Immunohistochemical staining for FOXP1 was performed in 126 familial breast carcinomas comprising 35 BRCA1, 34 BRCA2 and 57 BRCAX.Results:Nuclear FOXP1 expression ranged from focal weak to widespread strong expression. Expression of FOXP1 was higher in familial breast cancers (54%) compared with sporadic cancers (46%) (p0.05). The absence of FOXP1 expression was associated with a shorter relapse-free (p = 0.025) and overall survival (p = 0.009) in familial breast cancer. Negativity for FOXP1 was associated with a significantly worse overall survival in BRCA2 cancers (p = 0.021) and there was a non-significant separation of the survival curves for BRCA1 cancers (p = 0.183). No differences in survival were seen for BRCAX cancers (p = 0.762).Conclusion:Results suggest that FOXP1 demonstrates different expression patterns in familial breast cancers than sporadic tumours, even in tumours showing similar phenotypes. They also suggest a different role of FOXP1 as a tumour suppressor in familial tumours, which is unrelated to ER expression and may impact on therapeutic options.

Background While a number of studies have examined miRNA profiles across the molecular subtypes of breast cancer, it is unclear whether BRCA1 basal-like cancers have a specific miRNA profile. This study aims to compare grade independent miRNA expression in luminal cancers, sporadic and BRCA1 basal-type breast cancers. It also aims to ascertain an immunohistochemical profile regulated by BRCA1 specific miRNAs for potential diagnostic use. Methods miRNA expression was assessed in 11 BRCA1 basal, 16 sporadic basal, 17 luminal grade 3 cancers via microarrays. The expression of Cyclin D1, FOXP1, FIH-1, pan-ERβ, NRP1 and CD99, predicted to be regulated by BRCA1 specific miRNAs by computer prediction algorithms, was assessed via immunohistochemistry in a cohort of 35 BRCA1 and 52 sporadic basal-like cancers. Assessment of cyclin D1, FOXP1, NRP1 and CD99 expression was repeated on a validation cohort of 82 BRCA1 and 65 sporadic basal-like breast cancers. Results Unsupervised clustering of basal cancers resulted in a “sporadic” cluster of 11 cancers, and a “BRCA1” cluster of 16 cancers, including a subgroup composed entirely of 10 BRCA1 cancers. Compared with sporadic basal cancers, BRCA1 cancers showed reduced positivity for proteins predicted to be regulated by miRNAs: FOXP1 (6/20[30 %] vs. 37/49[76 %], p

We present a case of lower back pain with lumbar nerve compromise due to a ligamentum flavum haematoma which was successfully treated surgically. A 62-year-old man was evaluated for lower back pain with associated leg pain and early signs of cauda equina syndrome. MRI of the lumbar spine demonstrated a contrast-enhancing mass adjacent to the lamina of L3 which was causing severe canal stenosis. Surgical excision of the lesion was recommended. The patient underwent an L3 laminectomy with excision of the epidural lesion. Histopathology showed it to be a haematoma of the ligamentum flavum with no untoward features. The patient recovered without complication.

Hypersensitivity pneumonitis (HP) is characterized by extensive interstitial lung inflammation primarily driven by activated T lymphocytes in response to exogenous antigens. The purpose of this study was to investigate whether chronic exposure to Acheta domesticus commonly known as house cricket was the underlying cause of HP in a 63 year old patient. HP was diagnosed by the history, spirometry high resolution computed tomography (HRCT) of the chest, bronchoalveolar lavage and trans-bronchial biopsy. Ouchterlony double diffusion assay, direct ELISA and Western blotting were used to detect immuno-reactive precipitins/antigens and anti-cricket antibodies. Mass spectrometry was used to identify the major putative antigens. T cell-mediated response to cricket antigens was assessed by in vitro cytokine production assays. HRCT showed extensive bilateral and ground glass opacification throughout the lungs with some sparing at the bases, while bronchoalveolar lavage showed lymphocyte predominant leukocyte infiltration. A lung biopsy showed diffuse chronic interstitial inflammation with poorly defined granulomas consisting lymphocytes and occasional giant cells. There were high titer antibodies against cricket protein extracts and specific antigen-antibody precipitins. Western blotting showed 4 specific immuno-reactive bands. Tryptic peptide digest and mass spectrometry revealed arginine kinase as a potential antigen. Multistep chromatography enriched cricket arginine kinase induced strong in-vitro interferon-γ response by PBMC obtained from the patient but not in other cricket-exposed and non-exposed healthy control subjects. This is the first study to report a case of subacute HP in response to prolonged exposure to house cricket antigens.

Extensive expression profiling studies have shown that sporadic breast cancer is composed of five clinically relevant molecular subtypes. However, although BRCA1-related tumours are known to be predominantly basal-like, there are few published data on other classes of familial breast tumours. We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumours by gene expression profiling and found that 74% BRCA1 tumours were basal-like, 73% of BRCA2 tumours were luminal A or B, and 52% non-BRCA1/2 tumours were luminal A. Thirty-four tumours were also analysed by single nucleotide polymorphism-comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumour was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumours were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumours (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumour suppressor genes were also detected, including in basal tumours (5q and 9p), and basal and luminal tumours (10q). This study highlights the heterogeneity of familial tumours and the clinical consequences for treatment and prognosis.

Introduction: RAD21 is a component of the cohesin complex, which is essential for chromosome segregation and error-free DNA repair. We assessed its prognostic and predictive power in a cohort of in situ and invasive breast cancers, and its effect on chemosensitivity in vitro. Methods: RAD21 immunohistochemistry was performed on 345 invasive and 60 pure in situ carcinomas. Integrated genomic and transcriptomic analyses were performed on a further 48 grade 3 invasive cancers. Chemosensitivity was assessed in breast cancer cell lines with an engineered spectrum of RAD21 expression. Results: RAD21 expression correlated with early relapse in all patients (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.06 to 2.86, P = 0.029). This was due to the effect of grade 3 tumors (but not grade 1 or 2) in which RAD21 expression correlated with early relapse in luminal (P = 0.040), basal (P = 0.018) and HER2 (P = 0.039) groups. In patients treated with chemotherapy, RAD21 expression was associated with shorter overall survival (P = 0.020). RAD21 mRNA expression correlated with DNA copy number, with amplification present in 32% (7/22) of luminal, 31% (4/13) of basal and 22% (2/9) of HER2 grade 3 cancers. Variations in RAD21 mRNA expression in the clinical samples were reflected in the gene expression data from 36 breast cancer cell lines. Knockdown of RAD21 in the MDA-MB-231 breast cancer cell line significantly enhanced sensitivity to cyclophosphamide, 5-fluorouracil and etoposide. The findings for the former two drugs recapitulated the clinical findings. Conclusions: RAD21 expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. RAD21 may be a novel therapeutic target.

Phyllodes tumours and cellular fibroadenomas are both fibroepithelial tumours of the breast. Phyllodes tumours, unlike fibroadenomas, have the ability to recur and metastasise. Although these lesions can be distinguished by their stromal cellularity, mitotic index, presence or absence of stromal overgrowth and cellular atypia, there is overlap and not infrequently a definitive diagnosis cannot be made, particularly on biopsy. We sought to evaluate whether DNA promoter methylation profiling using selected genes known to be methylated in cancer would allow us to learn more about the biology of these tumours, and whether it could identify methylation markers that could differentiate phyllodes tumours from fibroadenomas and/or distinguish phyllodes tumours of different grades. Methylation-sensitive high resolution melting (MS-HRM) was used to screen promoter DNA methylation changes in 86 phyllodes tumours (15 benign, 28 borderline, 43 malignant) and 26 fibroadenomas. A panel of 11 genes (RASSF1A, TWIST1, APC, WIF1, MGMT, MAL, RARβ, CDKN2A, CDH1,TP73 and MLH1) was tested. Methylation status was correlated with histology and with clinicopathological parameters. Five of the gene promoters showed some methylation in a proportion of phyllodes tumours; RASSF1A, 45.3%; TWIST1, 10.7%; APC, 4.1%; WIF1, 2.9% and MGMT, 1.3%. Only two genes showed any methylation in fibroadenomas usually at background levels; RASSF1A, 53.8% and MGMT, 8.3%. No CDKN2A methylation was observed in either tumour type, contrary to previous reports. Overall, the methylation patterns differed little from that which might be seen in normal cells. However, significant levels of methylation of RASSF1A (24.4%) and TWIST1 (7.1%) was observed in some phyllodes tumours. Elevated RASSF1A and/or TWIST1 methylation was significantly associated with phyllodes tumours compared with fibroadenomas (P = 0.02), TWIST1 methylation correlated with increasing malignancy in phyllodes tumours (P < 0.001). In conclusion, assessment of methylation of RASSF1A and TWIST1 may aid in the diagnosis of phyllodes tumours. The absence of frequent methylation in fibroadenomas supports a non-neoplastic origin.

504 Background: Gene expression profiling has identified four main intrinsic subtypes of breast cancer which have distinct clinical behaviours and responses to therapy. A simplified immunohistochemical (IHC) panel can provide meaningful discrimination and help guide patient management. Methods: Using tissue microarrays (TMA) created from two randomized trials of adjuvant chemoendocrine therapy in node negative early breast cancer (IBCSG VIII and IX,n= 1220) we assessed intrinsic subtype as follows: “luminal A” (LA): ER and/or PR present, Ki-67 low (=19% median) and/or HER2+ (IHC 3+ or FISH amplified); HER2 enriched: ER and PR negative, HER2 positive (IHC 3+ or FISH amplified), Triple Negative (TNP): ER, PR and HER2 negative. p53+ and high cyclin D1 expression were then assessed to determine if they provided any further additive discriminatory value. Results: The standard definitions of intrinsic subtype demonstrated a significant difference in disease-free survival between the subtypes in both trials VIII and IX (p= 0.02), but this was not significant in multivariate analysis. The discrimination between luminal A and B tumors could not be improved upon by the addition of p53 or cyclin D1 expression. The standard definitions demonstrated that TNP and HER2-enriched tumors benefited from the addition of chemotherapy to endocrine therapy, but LA and LB did not. p53+ was associated with a poorer prognosis in ER+ luminal tumors but improved prognosis in ER- non-luminal tumors (Interaction p = 0.002). Conclusions: Intrinsic subtyping using a panel of ER, PR, HER2 and Ki67 provides meaningful prognostic information to help guide patient management in early breast cancer. Whilst it predicts benefit from the addition of chemotherapy in TNP and HER2-enriched tumors it did not in this series do so for LB. Although p53 status did not improve the definition of luminal tumors, p53+ appeared to have a divergent effect on outcome dependent on ER status.

Introduction The RAD21 gene encodes a key component of the cohesin complex, which is essential for chromosome segregation, and together with BRCA1 and BRCA2, for high-fidelity DNA repair by homologous recombination. Although its expression correlates with early relapse and treatment resistance in sporadic breast cancers, it is unclear whether familial breast cancers behave in a similar manner. Methods We performed an immunohistochemical analysis of RAD21 expression in a cohort of 94 familial breast cancers (28 BRCA1, 27 BRCA2, and 39 BRCAX) and correlated these data with genotype and clinicopathologic parameters, including survival. In these cancers, we also correlated RAD21 expression with genomic expression profiling and gene copy-number changes and miRNAs predicted to target RAD21. Results No significant differences in nuclear RAD21 expression were observed between BRCA1 (12 (43%) of 28), BRCA2 (12 (44%) of 27), and BRCAX cancers (12 (33%) of 39 (p = 0.598). No correlation was found between RAD21 expression and grade, size, or lymph node, ER, or HER2 status (all P > 0.05). As for sporadic breast cancers, RAD21 expression correlated with shorter survival in grade 3 (P = 0.009) and but not in grade 1 (P = 0.065) or 2 cancers (P = 0.090). Expression of RAD21 correlated with poorer survival in patients treated with chemotherapy (P = 0.036) but not with hormonal therapy (P = 0.881). RAD21 expression correlated with shorter survival in BRCA2 (P = 0.006) and BRCAX (P = 0.008), but not BRCA1 cancers (P = 0.713). Changes in RAD21 mRNA were reflected by genomic changes in DNA copy number (P < 0.001) and by RAD21 protein expression, as assessed with immunohistochemistry (P = 0.047). High RAD21 expression was associated with genomic instability, as assessed by the total number of base pairs affected by genomic change (P = 0.048). Of 15 miRNAs predicted to target RAD21, mir-299-5p inversely correlated with RAD21 expression (P = 0.002). Conclusions Potential use of RAD21 as a predictive and prognostic marker in familial breast cancers is hence feasible and may therefore take into account the patient's BRCA1/2 mutation status.

Aim It is recognised that oestrogens mediate their key role in the development and progression of breast cancer through two transcription factors, oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERβ). ERα has been studied extensively in familial breast cancers but there are limited data on ERβ. Here, we present a larger study looking at the impact of ERβ expression on clinical outcome and on different molecular subtypes of familial breast cancer. Methods Immunohistochemical study of ERβ in a cohort of 139 familial breast carcinomas as tissue microarray was done and compared with a cohort of 186 sporadic cancers collected. Sections were stained with mouse ERβ monoclonal antibody 14C8 (Abcam). Results A significant proportion of BRCA1 and basal-like familial breast carcinomas that are ERα negative, express ERβ. High cytoplasmic ERβ expression in familial basal-like cancers was significantly associated with shorter overall survival, but not relapse free survival. Conclusion Currently therapeutic and prognostic targets for breast cancer are exclusively dependent on the presence of the ERα. We propose, ERβ should be assessed and tamoxifen or other hormonal therapies should be considered in such patients that demonstrate ERβ positivity.