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1. The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype: Human Pathology, Vol. 39, No. 10. (October 2008), pp. 1431-1437.Summ ary Gene expression studies have identified a basal phenotype of breast cancer; these are hormone receptor and HER2-negative cancers with poor prognosis. High levels of cyclin E and Skp2, and low levels of p27 have previously been individually associated with both basal-like breast cancer and a poor outcome after diagnosis. The goal of this study was to first confirm the prognostic value of these biomolecular markers using a breast cancer tissue microarray. Second, we also test the hypothesis that the combined phenotype of high cyclin E, low p27, and high Skp2 would be a strong predictor of outcome and would be closely associated with the basal phenotype of breast cancer. Our cohort consisted of 438 cases of breast cancer and the median follow-up was 15.4 years. The tissue microarray was constructed from archival tumor blocks and we used commercially available antibodies for biomarker immunostaining . Cyclin E was positive in 46% of cases, p27 was negative in 62%, and Skp2 was positive in 35%. We found cyclin E and Skp2 to be prognostic for breast cancer-specifi c survival in univariate analyses, but p27 was not prognostic. The strongest predictor of outcome was the combination of cyclin E positive and Skp2 positive (difference in survival of 19% at 10 years, P = .0009). This combination was present in 78 (27%) of 288 cases for which data on both biomarkers were available. This combination was also highly associated with young age at diagnosis, grade 3 tumors, ER-negative status, HER2-negative status, and the basal biomarkers epidermal growth factor receptor and cytokeratin 5/6. However, in a multivariate model including standard clinicopatholo gic variables, this combination was not found to have independent prognostic significance. In conclusion, the combination of high cyclin E and Skp2 expression predicts for poor prognosis in breast cancer in univariate analysis only, it is associated with high risk features, and it is associated with the basal phenotype.Davi d Voduc, Torsten Nielsen, Maggie Cheang, William Foulkes
   
   Source: Human Pathology, Vol. 39, No. 10. (October 2008), pp. 1431-1437.
   
   
2. Frequency of the basal-like phenotype in African breast cancer: Apmis, Vol. 115, No. 12. (December 2007), pp. 1391-1399.Basa l-like breast carcinoma has been recognized as a subtype with specific prognostic implications. However, there is a lack of reports about this category of breast tumors in African women. The aim of this study was to explore the basal-like phenotype in breast cancer patients in an African population, and a registry-based series was included from the well-defined Kyadondo County in Uganda (1.7 millions). We studied a total of 65 archival paraffin blocks of invasive breast cancer using antibodies against cytokeratin 5/6 and P-cadherin, and these markers were expressed in 34% of all cases and in 52% of ER (estrogen receptor)-nega tive tumors. All basal-like tumors were ER negative (p
   
   Source: Apmis, Vol. 115, No. 12. (December 2007), pp. 1391-1399.
   
   
3. Prognostic effect of Basal-like breast cancers is time dependent: evidence from tissue microarray studies on a lymph node-negative cohort.: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 14, No. 13. (1 July 2008), pp. 4168-4174.PURP OSE: To determine whether data obtained from tissue microarrays (TMA) of a prospectively accrued node-negative breast cancer cohort are prognostically informative, we compared data derived from TMA with previously determined molecular markers. Subsequent to this validation, we examined outcome in specific subgroups defined using TMA data. EXPERIMENTAL DESIGN: A consecutive series of 1,561 patients were followed for recurrence (median follow-up of 107 months). Estrogen receptor, progesterone receptor, p53, and HER2 expression, examined using TMA constructed from 887 tumors, was compared with status evaluated previously by biochemical and molecular methods. The associations with risk of recurrence were examined for biomarkers as well as for HER2, luminal, and basal subgroups defined by immunohistoche mical expression. RESULTS: In line with earlier molecular studies, a significant risk of recurrence was found in patients with HER2 overexpression (relative risk = 2.30; P = 0.002) and p53-positive tumors (relative risk = 1.81; P = 0.005) in univariate Cox model analysis. Although complete concordance between methodologies was not observed for estrogen receptor and progesterone receptor, their associations with disease-free survival were consistent with established prognostic findings. Patients with basal-type tumors fared worse within 36 months of diagnosis but not thereafter. CONCLUSIONS: This study shows the clinical validity of TMA in evaluating the importance of prognostic markers in this cohort. Furthermore, it shows a marked time-dependent effect in tumor subgroups, most notable within the basal subgroup. Our data suggest that patients with basal-like tumors may be broadly separable into two clinically distinctive groups: those likely to experience disease recurrence in the short term and those that will experience long-term survival.AM Mulligan, D Pinnaduwage, SB Bull, FP O'Malley, IL Andrulis
   
   Source: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 14, No. 13. (1 July 2008), pp. 4168-4174.
   
   
4. Epidemiology of basal-like breast cancer.: Breast cancer research and treatment, Vol. 109, No. 1. (May 2008), pp. 123-139.Risk factors for the newly identified "intrinsic" breast cancer subtypes (luminal A, luminal B, basal-like and human epidermal growth factor receptor 2-positive/est rogen receptor-negat ive) were determined in the Carolina Breast Cancer Study, a population-bas ed, case-control study of African-Americ an and white women. Immunohistoche mical markers were used to subtype 1,424 cases of invasive and in situ breast cancer, and case subtypes were compared to 2,022 controls. Luminal A, the most common subtype, exhibited risk factors typically reported for breast cancer in previous studies, including inverse associations for increased parity and younger age at first full-term pregnancy. Basal-like cases exhibited several associations that were opposite to those observed for luminal A, including increased risk for parity and younger age at first term full-term pregnancy. Longer duration breastfeeding, increasing number of children breastfed, and increasing number of months breastfeeding per child were each associated with reduced risk of basal-like breast cancer, but not luminal A. Women with multiple live births who did not breastfeed and women who used medications to suppress lactation were at increased risk of basal-like, but not luminal A, breast cancer. Elevated waist-hip ratio was associated with increased risk of luminal A in postmenopausal women, and increased risk of basal-like breast cancer in pre- and postmenopausal women. The prevalence of basal-like breast cancer was highest among premenopausal African-Americ an women, who also showed the highest prevalence of basal-like risk factors. Among younger African-Americ an women, we estimate that up to 68% of basal-like breast cancer could be prevented by promoting breastfeeding and reducing abdominal adiposity.RC Millikan, B Newman, CK Tse, PG Moorman, K Conway, LV Smith, MH Labbok, J Geradts, JT Bensen, S Jackson, S Nyante, C Livasy, L Carey, HS Earp, CM Perou
   
   Source: Breast cancer research and treatment, Vol. 109, No. 1. (May 2008), pp. 123-139.
   
   
5. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negativ e phenotype.: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 14, No. 5. (1 March 2008), pp. 1368-1376.PURP OSE: Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negativ e phenotype definition [estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2, all negative] is commonly used to identify such cases. EGFR and cytokeratin 5/6 are readily available positive markers of basal-like breast cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three- and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series of breast tumors. EXPERIMENTAL DESIGN: Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment, and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistoche mical panels. RESULTS: Among 3,744 interpretable cases, 17% were basal using the triple-negativ e definition (10-year BCSS, 6 7%) and 9% were basal using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis of triple-negativ e phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negativ e patients treated with adjuvant anthracycline- based chemotherapy, the additional positive basal markers identified a cohort of patients with significantly worse outcome. CONCLUSIONS: The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and cytokeratin 5/6 provides a more specific definition of basal-like breast cancer that better predicts breast cancer survival.MC Cheang, D Voduc, C Bajdik, S Leung, S McKinney, SK Chia, CM Perou, TO Nielsen
   
   Source: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 14, No. 5. (1 March 2008), pp. 1368-1376.
   
   
6. Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants: The Value of Cytokeratin Profiles and Evolutionary Analysis--A Report From the kConFab Investigators: J Clin Oncol, Vol. 26, No. 10. (1 April 2008), pp. 1657-1663.Purp oseRare missense substitutions and in-frame deletions of BRCA1 and BRCA2 genes present a challenge for genetic counseling of individuals carrying such unclassified variants. We assessed the value of tumor immunohistoche mical markers in conjunction with genetic and evolutionary approaches for investigating the clinical significance of unclassified variants. Patients and MethodsWe studied 10 BRCA1 and 12 BRCA2 variants identified in Australian families with breast cancer. Analyses assumed a prior probability based on revised cross-species sequence alignment methods assessing amino acid evolutionary conservation and position, combined with likelihoods from data on co-occurrence with pathogenic mutations in the same gene, segregation analysis, and immunohistoche mistry. We specifically explored the value of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 as tumor markers of BRCA1 mutation status. ResultsPosteri or probabilities classified 72% of variants. BRCA1 variants IVS18+1 G>T (del exon 18) and 5632 T >A (V1838E) were classified as pathogenic, with >99% posterior probability of being deleterious, and tumor histopathology was particularly important for their classification . BRCA2 variant classification was improved over previous studies, largely by incorporating the prior probability of pathogenicity based on amino acid cross-species sequence alignments. ConclusionVari ant classification was considerably improved by analysis of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumor expression, and use of updated methods estimating the clinical relevance of amino acid evolutionary conservation and position. These methodologies may assist genetic counseling of individuals with unclassified sequence variants. 10.1200/JCO.20 07.13.2779Aman da Spurdle, Sunil Lakhani, Sue Healey, Suzanne Parry, Leonard Da Silva, Ross Brinkworth, John Hopper, Melissa Brown, Davit Babikyan, Georgia Chenevix-Trenc h, Sean Tavtigian, David Goldgar
   
   Source: J Clin Oncol, Vol. 26, No. 10. (1 April 2008), pp. 1657-1663.
   
   
7. Is 'basal-like' carcinoma of the breast a distinct clinicopatholo gical entity? A critical review with cautionary notes.: Pathobiology : journal of immunopatholog y, molecular and cellular biology, Vol. 75, No. 2. (2008), pp. 119-131.This review deals with studies that have used cDNA microarrays and immunohistoche mistry to identify a subtype of breast carcinoma known as basal-like carcinoma. The key breast carcinoma studies are critically discussed to highlight methodological problems in cohort selection, definitions, interpretation of results and statistical analysis. The review concludes that basal-like carcinomas do not reflect a single, biologically uniform group of breast cancers, but show significant variations in their phenotypes, grades, immunoprofiles and clinical behavior, just as a wide range of subtypes and behaviors is observed among epithelial/lum inal-derived breast carcinomas. Well-designed studies with comparison of low-grade nonbasal versus low-grade basal and high-grade nonbasal versus high-grade basal carcinomas are necessary before one can be convinced that this subtype represents a distinct clinicopatholo gical entity.F Moinfar
   
   Source: Pathobiology : journal of immunopathology, molecular and cellular biology, Vol. 75, No. 2. (2008), pp. 119-131.
   
   
8. The substantia nigra pars compacta and temporal processing.: J Neurosci, Vol. 26, No. 47. (22 November 2006), pp. 12266-12273.Th e basal ganglia and cerebellum are considered to play a role in timing, although their differential roles in timing remain unclear. It has been proposed that the timing of short milliseconds-r ange intervals involves the cerebellum, whereas longer seconds-range intervals engage the basal ganglia (Ivry, 1996). We tested this hypothesis using positron emission tomography to measure regional cerebral blood flow in eight right-handed males during estimation and reproduction of long and short intervals. Subjects performed three tasks: (1) reproduction of a short 500 ms interval, (2) reproduction of a long 2 s interval, and (3) a control simple reaction time (RT) task. We compared the two time reproduction tasks with the control RT task to investigate activity associated with temporal processing once additional cognitive, motor, or sensory processing was controlled. We found foci in the left substantia nigra and the left lateral premotor cortex to be significantly more activated in the time reproduction tasks than the control RT task. The left caudate nucleus and right cerebellum were more active in the short relative to the long interval, whereas greater activation of the right putamen and right cerebellum occurred in the long rather than the short interval. These results suggest that the basal ganglia and the cerebellum are engaged by reproduction of both long and short intervals but play different roles. The fundamental role of the substantia nigra in temporal processing is discussed in relation to previous animal lesion studies and evidence for the modulating influence of dopamine on temporal processing.M Jahanshahi, CR Jones, G Dirnberger, CD Frith
   
   Source: J Neurosci, Vol. 26, No. 47. (22 November 2006), pp. 12266-12273.
   
   
9. Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle.: Am J Physiol Lung Cell Mol Physiol, Vol. 291, No. 3. (September 2006)Chronic airways diseases, including asthma, are associated with an increased airway smooth muscle (ASM) mass, which may contribute to chronic airway hyperresponsiv eness. Increased muscle mass is due, in part, to increased ASM proliferation, although the precise molecular mechanisms for this response are not completely clear. Caveolae, which are abundant in smooth muscle cells, are membrane microdomains where receptors and signaling effectors can be sequestered. We hypothesized that caveolae and caveolin-1 play an important regulatory role in ASM proliferation. Therefore, we investigated their role in p42/p44 MAPK signaling and proliferation using human ASM cell lines. Disruption of caveolae using methyl-beta-cy clodextrin and small interfering (si)RNA-knockd own of caveolin-1 caused spontaneous p42/p44 MAPK activation; additionally, caveolin-1 siRNA induced ASM proliferation in mitogen deficient conditions, suggesting a key role for caveolae and caveolin-1 in maintaining quiescence. Moreover, caveolin-1 accumulates twofold in myocytes induced to a contractile phenotype compared with proliferating ASM cells. Caveolin-1 siRNA failed to increase PDGF-induced p42/p44 MAPK activation and cell proliferation, however, indicating that PDGF stimulation actively reversed the antimitogenic control by caveolin-1. Notably, the PDGF induced loss of antimitogenic control by caveolin-1 coincided with a marked increase in caveolin-1 phosphorylatio n. Furthermore, the strong association of PDGF receptor-beta with caveolin-1 that exists in quiescent cells was rapidly and markedly reduced with agonist addition. This suggests a dynamic relationship in which mitogen stimulation actively reverses caveolin-1 suppression of p42/p44 MAPK signal transduction. As such, caveolae and caveolin-1 coordinate PDGF receptor signaling, leading to myocyte proliferation, and inhibit constitutive activity of p42/p44 MAPK to sustain cell quiescence.R Gosens, GL Stelmack, G Dueck, KD McNeill, A Yamasaki, WT Gerthoffer, H Unruh, AS Gounni, J Zaagsma, AJ Halayko
   
   Source: Am J Physiol Lung Cell Mol Physiol, Vol. 291, No. 3. (September 2006)
   
   
10. Structure Mapping And Semantic Integration in a Construction-B ased Neurolinguisti c Model of Sentence Processing: Cortex, Vol. 42, No. 4. (2006), pp. 476-479.The current research provides a theoretical, computational and neurophysiolog ical framework in which particular aspects of sentence comprehension and non-linguistic sequence transformation processing are implemented by a common neural mechanism for structure mapping. The theoretical context is derived from construction grammar theory in which language is considered in terms of a structured inventory of form to meaning mappings. Computationall y, the construction grammar concept is implemented in a hybrid neural network model that is derived from functional neuroanatomica l studies. In particular, based on data from Hoen et al. (2006, this issue), the generalized structure mapping capability is attributed to a local cortical network that includes Brodmann's area (BA) 44, while the integration of semantic structure into this transformation mechanism relies on BA 45.Peter Dominey, Michel Hoen
    
    Source: Cortex, Vol. 42, No. 4. (2006), pp. 476-479.
    
    

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