76 research outputs found
Basal-like breast cancers: from pathology to biology and back again
Human breast cancers referred to as "basal-like" are of interest because they lack effective therapies and their biology is poorly understood. The term basal-like derives from studies demonstrating tumor gene expression profiles that include some transcripts characteristic of the basal cells of the normal adult human mammary gland and others associated with a subset of normal luminal cells. Elucidating the mechanisms responsible for the profiles of basal-like tumors is an active area of investigation. More refined molecular analysis of patients' samples and genetic strategies to produce breast cancers de novo from defined populations of normal mouse mammary cells have served as complementary approaches to identify relevant pathway alterations. However, both also have limitations. Here, we review some of the underlying reasons, including the unifying concept that some normal luminal cells have both luminal and basal features, as well as some emerging new avenues of investigation
The receptor protein tyrosine phosphatase PTPRB negatively regulates FGF2-dependent branching morphogenesis
PTPRB is a transmembrane protein tyrosine phosphatase known to regulate blood vessel remodelling and angiogenesis. Here we demonstrate that PTPRB negatively regulates branching morphogenesis in the mammary epithelium. We show that Ptprb is highly expressed in adult mammary stem cells and also, although at lower levels, in estrogen receptor positive luminal cells. During mammary development Ptprb expression is down-regulated during puberty, a period of extensive of ductal outgrowth and branching. In vivo shRNA knockdown of Ptprb in the cleared mammary fat pad transplant assay resulted in smaller epithelial outgrowths with an increased branching density and also increased branching in an in vitro organoid assay. Organoid branching was dependent on stimulation by FGF2, and Ptprb knockdown in mammary epithelial cells resulted in a higher level of FGFR activation and ERK1/2 phosphorylation, both at baseline and following FGF2 stimulation. Therefore, PTPRB regulates branching morphogenesis in the mammary epithelium by modulating the response of the FGFR signalling pathway to FGF stimulation. Considering the importance of branching morphogenesis in multiple taxa, our findings have general importance outside mammary developmental biology
Ki-67 Expression in Breast Cancer; Its Association with Grading Systems, Clinical Parameters and Other Prognostic Factors -- A Surrogate Marker?
BACKGROUND. The number of mitoses and, thus, the proliferative capacity of a tumor
is one of the most crucial variables for tumor grading. The Ki-67 nuclear antigen may
be considered as an alternative to mitotic counts in grading schemes and as a single
parameter that can be used in fine-needle aspirates and small biopsies.
METHODS. Immunohistochemistry using the anti-Ki-67 antibody MIB-1 was performed
on 434 breast carcinoma specimens from the International Breast Cancer
Study Group (formerly Ludwig) Trial V. Three groups based on Ki-67 percent were
used to replace the mitotic counts component in the Nottingham grade (NHG) to
produce the Nottingham/Ki-67 grade (NKG) and to assess Ki-67 as a single parameter.
RESULTS. In both the lymph node positive subgroup and the lymph node negative
subgroup, the NKG and Ki-67 group was correlated significantly with Bloomâ
Richardson grade (BRG), NHG, and Nottingham type. Tumor size in the lymph
node negative cohort and estrogen receptor status, progesterone receptor status,
and c-erbB-2 expression in the lymph node positive cohort also were correlated
significantly with NKG. Ki-67 percentage was correlated significantly with c-erbB-2
expression in the lymph node positive cohort only. NKG was similar to BRG and
NHG when it was evaluated for prognostic significance. Patients with higher
categoric Ki-67 percentages had worse overall and disease free survival in all
groups except for the untreated, lymph node negative group.
CONCLUSIONS. Ki-67 detection represents a valuable tool and is a good objective
substitute for mitotic counts when used in a grading system. When it is used alone,
Ki-67 detection provides valuable information, although it is necessary to combine
this with other parameters in the study of core biopsies and fine-needle aspirates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91948/1/2003 Cancer Ki-67 Expression in Breast Carcinoma.pd
A prophylactic vaccine for breast cancer?
Cancer vaccines are the Holy Grail for patients and clinicians alike. The possibility that we can be vaccinated against common cancers is very appealing and the socioeconomic consequences are significant. A recent paper from Vincent Tuohy's group, published in the journal Nature Medicine, suggests a new approach for the development of a prophylactic vaccine for breast cancer. Their strategy was to induce mammary gland failure in mice by immunisation with an antibody specific to a milk protein that resulted in autoimmunity during lactation. This also showed some efficacy as a therapeutic vaccine. Can we look forward to the elimination of breast cancer
Rethinking access: key methodological challenges in studying energy companies
Understanding the role of large energy corporations in society is a crucial, yet challenging task for the social
science of energy. Ethnographic methods hold potential for plying into corporationsâ own self-representations,
to reveal the relations of power and politics that determine flows of energy and extractive capital at the global
and local level. Ethnography help us move beyond structural analyses, to locate the agents and processes at work
within economies of energy production, and identify tensions and dynamics both within the corporation and at
the interface with society. We argue that a multi-method and reflexive approach can help social scientists reflect
on frictions in corporate encounters, and more importantly that attention to frictions is in fact a gateway to gain
new insights about the field. In our research project about Norwegian energy companies and their corporate social
responsibility work when âgoing globalâ, applying a multi-method made us question dominant assumptions
within anthropology of what constitutes âaccessâ. We discuss how multiple approaches to âaccessâ, which takes
into account the positionality of the researcher, fluidity of research fields along with attention to power dynamics
can shape the sort of knowledge that is produced when studying energy companies
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Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX
Introduction: The prognostic significance of p53 protein expression in early breast cancer remains uncertain, with some but not all studies finding an association with poorer outcomes. Estrogen receptor (ER) expression is both a positive prognostic marker and predictive of response to endocrine therapies. The relationship between these biomarkers is unknown. Methods: We constructed tissue microarrays (TMAs) from available pathological material from 1113 patients participating in two randomized clinical trials comparing endocrine therapy alone versus chemo-endocrine therapy in node-negative breast cancer. Expression of p53 defined as >10% positive nuclei was analyzed together with prior immunohistochemical assays of ER performed at central pathological review of whole tumor sections. Results: ER was present (i.e. >1% positive tumor cell nuclei) in 80.1% (880/1092). p53 expression was significantly more frequent when ER was absent, 125/212 (59%) than when ER was present, 171/880 (19%), p <0.0001. A significant qualitative interaction was observed such that p53 expression was associated with better disease-free survival (DFS) and overall survival (OS) among patients whose tumors did not express ER, but worse DFS and OS among patients whose tumors expressed ER. The interaction remained significant after allowance for pathologic variables, and treatment. Similar effects were seen when luminal and non-luminal intrinsic subtypes were compared. Conclusions: Interpretation of the prognostic significance of p53 expression requires knowledge of concurrent expression of ER. The reason for the interaction between p53 and ER is unknown but may reflect qualitatively different p53 mutations underlying the p53 expression in tumors with or without ER expression. Trial registration Current Controlled Trials ACTRN12607000037404 (Trial VIII) and ACTRN12607000029493 (Trial IX)
Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays
Background: Tumor levels of steroid hormone receptors, a factor used to select adjuvant treatment for early-stage breast cancer, are currently determined with immunohistochemical assays. These assays have a discordance of 10%-30% with previously used extraction assays. We assessed the concordance and predictive value of hormone receptor status as determined by immunohistochemical and extraction assays on specimens from International Breast Cancer Study Group Trials VIII and IX. These trials predominantly used extraction assays and compared adjuvant chemoendocrine therapy with endocrine therapy alone among pre- and postmenopausal patients with lymph node-negative breast cancer. Trial conclusions were that combination therapy provided a benefit to pre- and postmenopausal patients with estrogen receptor (ER)-negative tumors but not to ER-positive postmenopausal patients. ER-positive premenopausal patients required further study. Methods: Tumor specimens from 571 premenopausal and 976 postmenopausal patients on which extraction assays had determined ER and progesterone receptor (PgR) levels before randomization from October 1, 1988, through October 1, 1999, were re-evaluated with an immunohistochemical assay in a central pathology laboratory. The endpoint was disease-free survival. Hazard ratios of recurrence or death for treatment comparisons were estimated with Cox proportional hazards regression models, and discriminatory ability was evaluated with the c index. All statistical tests were two-sided. Results: Concordance of hormone receptor status determined by both assays ranged from 74% (Îș = 0.48) for PgR among postmenopausal patients to 88% (Îș = 0.66) for ER in postmenopausal patients. Hazard ratio estimates were similar for the association between disease-free survival and ER status (among all patients) or PgR status (among postmenopausal patients) as determined by the two methods. However, among premenopausal patients treated with endocrine therapy alone, the discriminatory ability of PgR status as determined by immunohistochemical assay was statistically significantly better (c index = 0.60 versus 0.51; P = .003) than that determined by extraction assay, and so immunohistochemically determined PgR status could predict disease-free survival. Conclusions: Trial conclusions in which ER status (for all patients) or PgR status (for postmenopausal patients) was determined by immunohistochemical assay supported those determined by extraction assays. However, among premenopausal patients, trial conclusions drawn from PgR status differedâimmunohistochemically determined PgR status could predict response to endocrine therapy, unlike that determined by the extraction assa
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