| 1. |
- Sjödin, Anna, 1974-
(författare)
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Human secretoglobins in normal and neoplastic cells and tissues
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Secretoglobins is a newly described polypeptide family that has gained a lot of interest in human cancer and inflammation research. Although the first secretoglobin polypeptide was discovered more than 30 years ago, their physiological function is still not known. The aim of this thesis was to study the expression of secretoglobins in normal and neoplastic human cells and tissues, and to clarify their possible involvement in human cancer. We established sensitive and specific quantitative real-time RT-PCR assays for uteroglobin, lipophilins A, B, C, mammaglobin, HIN-1, and UGRP1, and developed specific antibodies for lipophilin B and mammaglobin. By using quantitative real-time RT-PCR, immunohistochemistry, Western blotting, and in situ hybridization, we studied secretoglobin expression in normal and neoplastic cells and tissues. In normal tissues, real-time RT-PCR analysis showed high expression of mammaglobin in skin. The mammaglobin expression in skin tissue was further confirmed by in situ hybridization and immunohistochemistry, and the expression was shown to be localized to the coiled gland cells of the eccrine sweat glands and the apocrine sweat glands. In addition, we showed by using Western blotting, that mammaglobin was secreted into perspiration from the eccrine sweat glands. In pituitary gland, immunohistochemical analysis showed that lipophilin B was expressed by approximately half of the cells in the anterior pituitary. By using quantitative real-time RT-PCR it was shown that both lipophilins B and C mRNA were expressed in the pituitary gland, therefore we suggested that lipophilins B and C form heterodimers in human pituitary. In neoplastic tissues, real-time RT-PCR analysis showed dysregulated secretoglobin expression in lung tumors, with down-regulation of uteroglobin and frequent up-regulation of lipophilins A, B, C, and mammaglobin. Immunohistochemical analyses showed down-regulation of mammaglobin in cylindromas versus non-neoplastic eccrine sweat glands and of lipophilin B in pituitary adenomas versus non-neoplastic anterior pituitary. The majority of investigated cell lines showed low, or most often, lack of secretoglobin expression. Nevertheless, it has been shown that mammaglobin is over-expressed in human breast carcinomas. However, ectopic over-expression of mammaglobin and/or lipophilin B had no appreciable effect on cell proliferation rates of Hs578T breast carcinoma cells in vitro. This does not exclude the possibility that secretoglobins could confer some advantage to tumor cells in vivo, but, it indicates that the reported over-expression of mammaglobin is an epiphenomenon not causally involved in breast carcinogenesis. In summary, our major findings were that mammaglobin was expressed and secreted by the sweat glands of the skin and lipophilin B was expressed by the anterior pituitary gland; and, that expression of mammaglobin and lipophilin B were down-regulated in tumors derived from the same tissues, i.e, in cylindromas and pituitary adenomas, respectively. Furthermore, ectopic over-expression of mammaglobin and lipophilin B in breast carcinoma cells had no appreciable effect on cell proliferation rates in vitro.
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| 2. |
- Niméus, Emma, et al.
(författare)
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Proteomic analysis identifies candidate proteins associated with distant recurrences in breast cancer after adjuvant chemotherapy.
- 2007
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Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085. ; 43:3, s. 1086-1093
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a heterogenous disease and it is of importance to select patients with regard to different prognosis and treatment sensitivity to individualize treatment regimes. In this study we successfully adapted a protein extraction protocol from mRNA extracted tumor samples enabling two-dimensional gel electrophoresis (2-DE) analysis of samples previously analyzed by cDNA microarray. The aim was to find candidate proteins that distinguish breast cancer patients with or without recurrences after adjuvant CMF (cyclophosphamide, methotrexate and 5-FU) treatment within four years to follow-up. We identified several proteins distinguishing the recurrence group from the non-recurrence group, especially in the ER and PgR positive subgroup (n = 7). The induced proteins were involved in translation/folding, iron ion binding, and protease inhibition, whereas proteins involved in signaling, ubiquitination, and splicing were decreased in expression. These results show that it is possible to use 2-DE to separate high abundant proteins in breast cancer tissue and to find discriminating proteins to identify patients with different prognosis after adjuvant CMF treatment.
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| 3. |
- Jögi, Annika, et al.
(författare)
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Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer
- 2009
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 22:12, s. 1564-1574
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Tidskriftsartikel (refereegranskat)abstract
- Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n = 1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (P<0.001), small tumors (P<0.001), estrogen receptor (ER) positivity (P<0.001) and Ki-67 negativity (P<0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30-0.79, P = 0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors. Modern Pathology (2009) 22, 1564-1574; doi:10.1038/modpathol.2009.124; published online 4 September 2009
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| 4. |
- Alkner, Sara, et al.
(författare)
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Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women : Results from a controlled randomised trial
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:14, s. 2496-2502
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial. Patients and methods: Premenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years. Results: In the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients less than40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40-49 years of age or ≥50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time. Conclusion: In this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women less than40 years of age. The effect of tamoxifen was not significantly dependent on time.
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| 5. |
- Berglund, Pontus, et al.
(författare)
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Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
- 2008
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
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| 6. |
- Jerevall, Piiha-Lotta, et al.
(författare)
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Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome
- 2008
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Ingår i: Breast Cancer Research and Treatment. - : Institutionen för klinisk och experimentell medicin. - 0167-6806 .- 1573-7217. ; 107:2, s. 225-234
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Tidskriftsartikel (refereegranskat)abstract
- Background: The two-gene expression ratio HOXB13:IL17BR has been proposed to predict the outcome of tamoxifen-treated breast cancer patients. We intended to examine whether this ratio can predict the benefit of 5 years vs. 2 years of tamoxifen treatment of postmenopausal patients. A further objective was to investigate any prognostic effects of the ratio in systemically untreated premenopausal patients. Based on the current knowledge of HOXB13 and IL17BR, we hypothesized that these genes may have individual prognostic or predictive power. Patients and methods: Expression of HOXB13 and IL17BR were quantified by real-time PCR in tumors from 264 randomized postmenopausal patients and 93 systemically untreated premenopausal patients. Results: A high HOXB13:IL17BR ratio was associated with aggressive tumor characteristics, as were low levels of IL17BR alone. The ratio and HOXB13 alone predicted recurrence-free survival after endocrine treatment, with a benefit of prolonged treatment in estrogen receptor-positive patients correlated to a low ratio (recurrence rate ratio: RR=0.39; p=0.030), or low expression of HOXB13 (RR=0.37; p=0.015). No difference in recurrence-free survival was seen for the high ratio or high HOXB13 subgroups. The predictive value of HOXB13 and HOXB13:IL17BR was significant in multivariate analysis. In the systemically untreated cohort, only IL17BR showed independent prognostic significance. Conclusion: We conclude that the ratio or HOXB13 alone can predict the benefit of endocrine therapy, with a high ratio or a high expression rendering patients less likely to respond. We have also shown that IL17BR might be an independent prognostic factor in breast cancer.
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| 7. |
- Jirström, Karin, et al.
(författare)
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Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial
- 2005
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:11, s. 1135-1142
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Tidskriftsartikel (refereegranskat)abstract
- Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
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| 8. |
- Niméus, Emma, et al.
(författare)
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Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionSome patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.MethodsWe performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.ResultsWithin the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).ConclusionA highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.
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| 9. |
- Rydén, Lisa, et al.
(författare)
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HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information
- 2008
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 109:2, s. 351-357
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOverexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status.MethodsPremenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61–5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28–1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved.DiscussionHER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.
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| 10. |
- Rydén, Lisa, et al.
(författare)
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Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer
- 2005
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 23:21, s. 4695-4704
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance.Patients and Methods Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors.Results VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status.Conclusion Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.
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