Biomedical subjects

Christopher R West

Publications and source records attributed to Christopher R West.

4 recordsLinked to original sources

PubMed2003

Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia.

It has been shown that the risk of breast cancer developing in certain morphologically identifiable benign breast lesions correlates with expression of estrogen receptor alpha (ER-alpha). Although ER-alpha and ER-beta genes share a large degree of homology, it is generally thought that their distribution and functions are substantially different in many tissues. Recent development of reliable antibodies to ER-beta has provided this first opportunity to test the hypothesis that the likelihood of malignant transformation in morphologically benign breast lesions can be accurately defined by the distribution and level of ER-beta expression relative to that of ER-alpha. Using a monoclonal antibody, ER-beta protein expression has been analyzed in 53 normal breasts and compared with a cohort of histologically distinct breast lesions of different prognostic risk (54 hyperplasia of usual type, 35 ductal carcinoma in situ, and 141 invasive cancers). All of these tissues were also assessed for ER-alpha. Expression of ER-beta protein was also analyzed in an additional spectrum of benign breast lesions with low or negligible risk of progression to malignancy. The median proportion of cells expressing ER-beta was highest in normal breast lobules (median 94.33%, interquartile range 78.25-99.00) but declined significantly through usual ductal hyperplasia (median 76.67, interquartile range 49.17-95.00, P = 0.002) and ductal carcinoma in situ (median 70.00, interquartile range 59.00-85.00, P = 0.009) to invasive cancer (median 60.00, interquartile range 50.00-80.00, P < 0.001). An appreciable proportion (33.81%) of ER-alpha-negative invasive cancers expressed ER-beta. A high but variable level of ER-beta expression occurred in the benign lesions. The data from the intact histologic tissues were evaluated with respect to the relative expression of ER-alpha and ER-beta in five mammary cell lines of different behavioral phenotype (MCF7, ZR-75, T47D, MDAMB231, HUMA121). The highly significant differences in expression and distinct tissue distributions of ER-alpha and ER-beta within the histologic lesions of defined risk, together with the data from the cell lines, support the original hypothesis that the tissue concentration, relative occurrence, and/or interaction of these two types of estrogen receptor may play an important role in modulating mammary tumorigenesis.

Blotting, Western↗

PubMed2002

Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer.

The adhesive glycophosphoprotein (OPN) is capable of inducing metastasis in rodent models ofbreast cancer. We now show that a monoclonal antibody to rat OPN recognizes specifically human OPN using Western blotting techniques andused it to assess the prognostic significance of OPN in primary tumors of a group of 333 patients treated between 1976 and 1982 for operable stage I and stage II breast cancer. The antibody stains immunocytochemically normal breast tissue weakly but pregnant/lactating tissue and 66% of the carcinomas strongly, leaving the remaining 34% as negatively stained. In addition to the carcinoma cells, some host reactive stromal cells, macrophages, lymphocytes, and blood vessels are also stained, but these have been excluded in the following analyses. There is a significant association of staining of carcinomas for OPN with some tumor variables reported previously to be associated with patient outcome: high histological grade (P = 0.024), staining for c-erbB-3 (P < 0.001), p53 (P = 0.014), pS2 (P = 0.025), and borderline significance for progesterone receptor (P = 0.089). The association of staining for OPN with survival times of the patients has been evaluated using life tables over 14-20 years of follow-up (mean 16 years) and analyzed using generalized Wilcoxon statistics. Of the patients who have been classified as OPN-negative, 94% are alive, but only 26% of those classified as OPN-positive are alive after 19 years of follow-up. This association is highly significant (P < 0.0001); the former have a median survival of >228 months and the latter 68 months. When the patients are divided into separate classes based on the percentage of carcinoma cells staining for OPN, the five classes show a progressive decrease in survival with increasing percentage of stained carcinoma cells, and this association is also highly significant (P < 0.0001). Other tumor variables that show a significant association with patient survival times in this group of patients include nodal status, tumor size, histological grade, staining for c-erbB-2, estrogen receptor alpha, or p53. Analysis of the association of patients with carcinomas staining for OPN and their survival in subgroups defined by these tumor variables shows that positive staining for OPN in each subgroup is associated with poorer survival. There is little difference in patient survival times in the OPN-negative group of patients with or without any of the other tumor variables examined. Multivariate regression analysis for 202 patients shows that staining for OPN is most highly correlated with patients' deaths (P < 0.0001), but involved lymph nodes (P = 0.0007), fixed tumors (P = 0.0008), and staining for estrogen receptor alpha (P = 0.008) are also significant independent prognostic variables with that for c-erbB-2 being of borderline significance (P = 0.060). These results suggest that in this group of patients, the presence of the metastasis-associated protein OPN is tightly correlated with patient demise.

Adult↗

PubMed2002

Breast cancer risk in usual ductal hyperplasia is defined by estrogen receptor-alpha and Ki-67 expression.

The hypothetical multistep model for breast carcinogenesis indicates that invasive carcinoma arises via a series of intermediate hyperplastic lesions through various grades of atypia to in situ and invasive carcinoma. Non-atypical hyperplasia [hyperplasia of usual type (HUT)] is a nonobligate precursor of breast cancer. Although its further morphological subclassification is unlikely, refining is more likely to depend on defining biological markers of risk. Having assembled a cohort of benign proliferative breast lesions of known outcome, we studied the expression of estrogen receptor-alpha (ER-alpha) and Ki-67 using morphometric image analysis as well as dual-labeled immunofluorescence in HUT foci and in surrounding normal lobules of 25 patients that progressed to breast cancer and 19 controls. Those patients that progressed to breast cancer (cases) showed significantly higher ER-alpha [median, 57.00% of cells within individual HUT foci; interquartile range (IQ), 33.48 to 67.78] and Ki-67 (median, 3.82%; IQ, 0.85 to 11.28) expression in their HUT foci compared with controls (ER-alpha median, 30.27%; IQ, 19.75 to 52.50 and Ki-67 median, 0.77%; IQ, 0.0458 to 1.72, P = 0.008 and <0.001). No significant difference in expression of dual-stained cells was found between cases and controls. Although normal lobules from cases showed higher ER-alpha expression compared with controls, this was not statistically significant. Our data point to a previously undescribed hormone-dependent pathway in this particular group of breast neoplasms and suggest the possibility of selective hormonal therapy to suppress the proliferative potential of these benign but high-risk breast lesions. The findings of this study might have important implications for improving breast cancer screening and management strategies.

Adult↗

PubMedDate not supplied

The human sperm head: a key for successful fertilization.

In order to examine the predictive value of determining the sperm head shape, the acrosomal size, the presence of acrosomal vacuoles, and the challenged acrosome reaction (AR) on the outcome of a standard in vitro fertilization (IVF) program, a prospective study was conducted that included 75 couples undergoing IVF treatment. An assessment of sperm morphology was performed using the Hobson Sperm Tracker (Hobson Tracker Limited, Sheffield, United Kingdom). The assessment of the AR was performed before and after adding pooled undiluted human follicular fluid (FF). The outcome measure was an IVF rate of inseminated oocytes. A positive correlation was found between the fertilization rate (FR%) and the proportion of the sperm with a normal (oval) head shape (P <.001), the sperm exhibiting acrosomal vacuoles (P <.003), the sperm with a normal acrosomal size (40%-70% of total head area, P <.025), and the sperm undergoing AR after adding FF (P <.001). Multiple logistic regression analysis revealed that by incorporating the above 4 parameters, the sensitivity of prediction of IVF FR% values was 79%, and the specificity was 93%, with a positive predictive value of 96%. This study shows that the multiparametric assessment of the sperm head is useful in predicting the FR% values of a standard IVF treatment. The automated analysis used in this study is shown to maintain a level of precision and accuracy acceptable for application in a routine semen analysis situation.

Acrosome↗