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1.
Global gene expression profiles, consisting mainly of genes associated with proliferation, have been shown to subdivide histological
grade 2 breast cancers into groups with different prognosis. We raised the question whether this subdivision could be done
using a single proliferation marker, cyclin A. Furthermore, we combined cyclin A (CA), histological grade (G), and estrogen
receptor—ER (E) into a new variable, CAGE. Our aim was to investigate not only the prognostic importance of cyclin A alone
but also the value of the combination variable CAGE. In 219 premenopausal node-negative patients, cyclin A was assessed using
immunohistochemistry on tissue microarrays. High cyclin A was defined as above the seventh decile of positive cells. Only
13% of the patients received adjuvant systemic therapy. Cox proportional hazards regression was used to model the impact of
the factors on distant disease-free survival (DDFS). Cyclin A divided histological grade 2 tumors into two groups with significantly
different DDFS (hazard ratio [HR]: 15, P < 0.001). When stratifying for ER status, cyclin A was a prognostic factor only in the ER positive subgroup. We found that
CAGE was an independent prognostic factor for DDFS in multivariate analysis (HR: 4.1, P = 0.002), together with HER2. CAGE and HER2 identified 53% as low-risk patients with a 5-year DDFS of 95%. A new prognostic
variable was created by combining cyclin A, histological grade, and ER (CAGE). CAGE together with HER2 identified a large
low-risk group for whom adjuvant chemotherapy will have limited efficacy and may be avoided. 相似文献
2.
Cyclin E has been shown to be overexpressed in some human breast cancers, however, data to support deregulation of cyclin
E as an early event in human mammary tumor development is lacking. We analyzed surgical specimens from 183 patients with breast
carcinomas and evaluated cyclin E expression in areas of invasive carcinoma, adjacent carcinoma in situ (CIS), and non-neoplastic
breast parenchyma. Overexpression of cyclin E was seen in one-third of invasive carcinoma samples, one-third of the CIS component
and nearly half of the non-neoplastic breast epithelial cells adjacent to carcinoma (44% vs. 33%, P ≤ 0.05). Nuclear labeling for cyclin E was highly concordant between areas of in invasive carcinoma, CIS and non-neoplastic
breast epithelial cells from the same patient ( P < 0.0001). Localization of cyclin E to the cytoplasm was seen in a small proportion of tumor samples. Our findings suggest
that cyclin E deregulation is an early event in the progression from histologically benign mammary epithelial cells to invasive
carcinoma and occurs through both overexpression and altered cellular localization. 相似文献
3.
Purpose Per2, a core circadian clock gene, has tumor suppressor properties and is mutated or down regulated in human breast cancers. We
have manipulated the expression of this gene in vitro and in vivo to more fully understand how the Per2 clock gene product affects cancer growth. Methods We used siRNA and shRNA to down regulate Per2 expression in vitro and in vivo and measured cancer cell proliferation, tumor growth rate and several molecular pathways
relevant to cancer growth and their circadian organizations. All statistical tests were two-sided. Results Down regulation of functional Per2 gene expression increases Cyclin D and Cyclin E levels and doubles in vitro breast cancer cell proliferation ( P < 0.05). Down regulation of Per2 also accelerates in vivo tumor growth and doubles the daily amplitude of the tumor growth rhythm ( P < 0.05). Conclusions The clock gene Per2 exerts its tumor suppressor function in a circadian time dependent manner. Therefore, Per2 and perhaps other clock genes represent a new class of potential therapeutic targets whose manipulation will modulate cancer
growth and cancer cell proliferation. 相似文献
4.
The authors have investigated the expression of the microcephalin (MCPH1) protein to evaluate its prognostic importance in
breast cancer. Microcephalin is a damage response protein involved in the regulation of BRCA1 and BRCA2. BRCA1 mutations are often associated with basal-like breast cancer, which are also often negative for oestrogen receptor (ER),
progesterone receptor (PR) and HER2. MCPH1 immunohistochemistry was performed on 319 breast cancers prepared as tissue microarray
and correlated with pathology, survival, ER, PR, HER2, EGFR, CK5/6, CK14 and BRCA1 expression. After performing continuous
data analysis, mean microcephalin expression decreased with increasing grade ( P < 0.006). Mean microcephalin expression was lower in ER/PR negative ( P < 0.001) and triple negative cancers ( P < 0.004). Conversely, an association with HER2-positive cancers was also identified ( P < 0.034). Reduced microcephalin also correlated with reduced nuclear BRCA1 staining ( P < 0.001). No association was identified with basal markers. After dichotomising the data into low and high microcephalin
expression, reduced expression was identified in 29% (93/319) of breast cancers. An association with low expression was identified
in invasive ductal carcinomas with breast cancer-specific survival (BCSS) ( P = 0.052). Multivariate analysis of ductal carcinomas showed that microcephalin, together with lymph node involvement and
tumour size were independent predictors of BCSS ( P = 0.037). Microcephalin expression is reduced in 29% of breast cancers, particularly in higher grade tumours and BRCA1-negative
cases. Microcephalin is an independent predictor of BCSS in invasive ductal breast cancer patients and may prove to be a useful
biomarker for the identification of aggressive breast cancers. 相似文献
5.
Objective To study the relationship between expressions of α-, β-catenins and cyclin D1 and the occurrence, infiltration and metastasis
of breast cancer.
Methods High sensitive S-P immunohistochemical method was used to detect the protein expressions of α-, β-catenins and cyclin D1 in
the 60 cases of breast cancer tissues.
Results Abnormal immunoreactivities of α-and β-catenins were observed in 37 (61.7%) and 42 (70%) cases of breast cancer tissues, respectively.
There were 28 cases (46.7%) who showed cyclin D1 overexpression. The abnormal expression rates of α-and β-catenins in infiltrating
lobular carcinoma (ILC) were significantly higher than those in infiltrating ductal carcinoma (IDC) ( P < 0.05), but they had no relations to the extent of differentiation and lymphatic metastasis of breast cancer ( P > 0.05). The overexpression rate of cyclin D1 was correlated with tumor stage and lymphatic metastasis of breast cancer ( P < 0.05), but not with histological type and the extent of differentiation ( P > 0.05). Cyclin D1 overexpression was observed in 57.1% (24/42) of these cases that showed abnormal staining of β-catenin,
but only observed in 22.2% (4/18) of these cases with normal membranous staining of β-catenin. There was a significantly positive
correlation between the abnormal expression of β-catenin and overexpression of cyclin D1 ( r
s = 0.321, P < 0.05).
Conclusion The abnormal expression of β-catenin may play an important role in the genesis of breast cancer by triggering cyclin D1 overexpression
in breast cancer. The abnormal expressions of α-and β-catenins are not a key factor in malignant cell metastasis in breast
cancer, but may also involve in the progress. 相似文献
6.
目的:探讨乳腺癌中Cyclin D1及p16蛋白表达的相关性及其临床意义。方法:LSAB法检测多种乳腺组织中Cyclin D1及p16蛋白的表达情况,结合有关临床资料,分析Cyclin D1和p16蛋白表达异常与乳腺癌中重要的临床病理因素的关系。结果:62例乳腺癌组织中,Cyclin D1蛋白过度表达占48·4%,其表达与乳腺癌组织学分级呈明显正相关,且Cyclin D1蛋白过度表达更常见于ER、PR阳性的乳腺癌中。乳腺癌旁组织中Cyclin D1蛋白过度表达为20·0%,其他几种乳腺组织很少有CyclinD1蛋白的过度表达。p16蛋白仅在58·1%的乳腺癌组织中有表达,且p16的表达与组织学分级程度有负相关关系。正常乳腺组织中未见p16蛋白的异常。结论:乳腺癌组织中存在着Cyclin D1蛋白的过度表达及p16蛋白的异常,二者对乳腺癌组织的增殖分化有一定的影响。 相似文献
7.
CCND1 encodes for the cyclin D1 protein involved in G1/S cell cycle transition. In breast cancer the mechanism of CCND1 amplification, relationship between cyclin D1 protein expression and the key clinical markers estrogen receptor (ER) and HER2 requires elucidation. Tissue microarrays of primary invasive breast cancer from 93 women were evaluated for CCND1 amplification by fluorescent in‐situ hybridization and cyclin D1 protein overexpression by immunohistochemistry. CCND1 amplification was identified in 27/93 (30%) cancers and 59/93 (63%) cancers had overexpression of cyclin D1. CCND1 amplification was significantly associated with cyclin D1 protein overexpression ( p < 0.001; Fisher's exact test) and both CCND1 amplification and cyclin D1 protein expression with oestrogen receptor (ER) expression ( p = 0.003 and p < 0.001; Fishers exact test). Neither CCND1 amplification nor cyclinD1 expression was associated with tumor size, pathological node status or HER2 amplification, but high CCND1 amplification (Copy Number Gain (CNG) ≥ 8) was associated with high tumor grade ( p = 0.005; chi square 7.915, 2 df) and worse prognosis by Nottingham Prognostic Index ( p = 0.001; 2 sample t‐test). High CCND1 amplification (CNG ≥ 8) may identify a subset of patients with poor prognosis ER‐positive breast cancers who should be considered for additional therapy. 相似文献
8.
Oestrogen receptor (ER) negative breast cancers are more likely to achieve a pathological complete response (pCR) to neoadjuvant
chemotherapy compared to those with ER positive tumours. ER positive tumours exhibit low proliferation and ER negative cancers
high proliferation. The aim of this study was to determine to what extent the better response of ER negative cancers correlates
with proliferation rate. A retrospective analysis of a prospectively maintained database identified 175 neoadjuvant chemotherapy
patients with tissue available for Ki67 analysis. On univariate analysis, pre-therapy Ki67 ( P = 0.04), ER status ( P = 0.002), HER2 status ( P = 0.004) and grade ( P = 0.0009) were associated with a pCR. In a multivariate model, HER2 was the only significant predictor of pCR. No significant
relationship between pre-therapy Ki67 and relapse-free and overall survival was demonstrated. Ki67 is not an independent predictor
of clinical CR or pCR. Aspects of ER status beyond its inverse relationship with proliferation may contribute to its predictive
value for pCR. 相似文献
9.
The main objective of this retrospective study was to investigate relations between cyclin E and pathoclinical factors in patients with operable breast cancer. Expression of cyclin E was analyzed by immunohistochemistry in specimens of invasive ductal breast cancer tissue obtained from 189 women during radical mastectomy. Overall, 110 tumor samples were regarded to be cyclin E positive. Cyclin E expression was more often seen in tumors with: negative steroid receptor status (p<0.0001), higher proliferative index (p=0.0014), higher tumor grade (p=0.0017), and presence of HER2 (p=0.0171). With a median follow-up of 58 months, expression of cyclin E together with negative steroid receptor status determined poor prognosis with a 5-year cancer-specific survival rate of 58%. It differed significantly from a survival curve of cyclin E negative and steroid receptor positive patients (87%, p=0.0005). No significant difference was observed in comparison with survival of cyclin E positive and steroid receptor positive patients (68%, p=0.221). We demonstrated that cyclin E expression in breast cancer cells was associated with negative steroid receptor status, HER2 presence, higher tumor grade and higher proliferation index. Expression of cyclin E together with lack of steroid receptors determined poor prognosis. 相似文献
10.
The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with locally advanced breast cancer (LABC). Two hundred and twenty consecutive patients with LABC who had received neoadjuvant chemotherapy (NCT) with docetaxel and epirubicin from March 2006 to March 2009 were included in this retrospective study. The pre- and post-neoadjuvant chemotherapy (NCT) treatment expression levels and changes of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). The pCR rate was 9.1% (95% CI, 5.3–12.9%). In univariate analysis, poor tumor differentiation, OR after 2 cycles of NCT, both negative of ER/PgR, negative HER-2, positive cyclin D1, and positive nm23-H1 were found to be significantly predictive of a pCR. Histological grade and ER/PgR status were significant for pCR on multivariate analysis (P = 0.023 and 0.003, respectively). The expression levels of cyclin D1 (median, 8% vs. 9%; P = 0.016) after NCT treatment increased significantly, while the median Ki-67 proliferation index was dramatically decreased after NCT treatment from 35 to 15% (P = 0.036). However, after a Bonferroni adjustment, only the difference of Ki-67 proliferation index was still significant (P = 0.026). Histological grade and ER/PgR status are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in locally advanced breast cancer. Expression of HER-2, Ki-67, cyclin D1, and nm23-H1 were not predictive for pCR. 相似文献
11.
The Notch ligand, JAG1 is associated with breast cancer recurrence. Herein, we report on a genomics approach to elucidate
mechanisms downstream of JAG1 that promote breast cancer growth. In a survey of 46 breast cancer cell lines, we found that
triple negative (TN; basal and mesenchymal ER-, PR-, and Her2-negative) lines express JAG1 at significantly higher levels
than do HER2 + or luminal (ER +) Her2 − cell lines. In contrast to the luminal lines tested (T47D and MCF7), TN breast cancer cell lines (HCC1143 and MDA MB231)
display high-level JAG1 expression and growth inhibition with RNA interference-induced JAG1 down-regulation. We used microarray
profiling of TN tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes ( P ≤ 0.005; fold change ≥1.5). Among JAG1-regulated genes identified, cyclin D1 was found to be a direct target of NOTCH1 and NOTCH3. We show that JAG1 down-regulation reduces direct binding of Notch to
the cyclin D1 promoter, reduced cyclin D1 expression and inhibition of cell cycle progression through the cyclin D1-dependant G1/S checkpoint.
Furthermore, we show that cyclin D1 and JAG1 expression correlate in TN breast cancer expression datasets. These data suggest
a model whereby JAG1 promotes cyclin D1-mediated proliferation of TN breast cancers. 相似文献
12.
Background. To elucidate the role that cyclin E overexpression plays in the progression of early gastric cancer, we examined the expression
of cyclin E and p53, as abnormal p53 expression is linked with cyclin E overexpression in exerting adverse affects on the cell cycle.
Methods. Specimens from 108 early gastric cancers were stained by an immunohistochemical method, using anti-cyclin E and anti- p53 antibodies.
Results. The positivity rate of cyclin E expression in early gastric cancer was 33% (36/108). Cyclin E-positive tumors invaded more
deeply ( P < 0.05), infiltrated lymphatic vessels more frequently ( P < 0.01), showed a higher incidence of differentiated cancer ( P < 0.01), and more often expressed p53 ( P < 0.01) than cyclin E-negative tumors. Differentiated cancers showing coexpression of cyclin E and p53 were more likely to metastasize to the lymph nodes.
Conclusions. Overexpression of cyclin E may promote the progression of early gastric cancer.
Received for publication on Apr. 27, 1998; accepted on Nov. 17, 1998 相似文献
13.
Objective To explore the distribution of estrogen receptors (ER) and progesterone receptors (PR) in patients with breast cancer and
to compare the results with clinical parameters.
Methods Breast cancer specimens of 1393 cases were stained for the ER and PR by a SP Two -Step method, and analyzed with respect to
age, menstrual status, histopathology and metastasis of axillary lymph nodes.
Results The correlation coefficients between ER and PR were positive-( P< 0.0001). The negative expression of ER in patients 39 years or less was the highest with a statistical significance ( P<0.0001 ). There was no relationship between the patient’s age and positive expression of ER, PR and negative expression of
PR ( P>0.05). There were significantly higher positive rates of ER and lower positive rates of PR in post-menopausaf patients than
in pre -menopausal cases( P<0.0001). There was no relationship between the status of ER, PR and the corresponding histopathology ( P>0.05). The patients with no metastasis in the axillary lymph nodes had higher simultaneous positive rates of ER and PR ( P<0.0001), and those with axillary lymph node metastasis had significantly higher rates of negative expression of ER and PR( P<0.0001).
Conclusion The positive and negative distributions of ER and PR have some regular patterns which may be used as a reference to choose
combined therapy and to predict the prognosis for breast cancer patients. 相似文献
14.
目的:研究正常乳腺上皮细胞与乳腺癌细胞之间以及不同恶性程度的乳腺癌细胞之间的细胞周期相关因子的表达异同。方法:采用Western印迹法检测正常乳腺细胞株AG11132A、ER阳性和乳腺癌细胞株MCF-7及ER阴性的乳腺癌细胞株MDA-MB-231之间细胞周期蛋白D1、E及P21蛋白表达的异同及与其生物学特性的关系。结果:(1)正常乳腺上皮细胞株高表达P21蛋白,低表达周期蛋白E。与正常细胞相比,乳腺癌细胞株MCF-7、MDA-MB-231细胞高表达周期蛋白E,其中表达的周期蛋白E中存在异常的你分子量周期蛋白E成分,而正常乳腺上皮细胞不表达这种异常 的周期蛋白E。(2)在乳腺癌细胞株之间,相对ER阳性的MCF-7细胞,ER阴性的MDA-MB-231细胞则高表达周期蛋白E,基本无表达P21蛋白。结论L(1)正常细胞与这间、相对低恶性程度的民相对高恶性和蔼的癌细胞之间的差别是多环节的、质和量异常导致的结果;(2)周期蛋白E及P21均可反映乳腺癌细胞的增殖活性和恶性程度,可能是乳腺癌的临床预后指标。 相似文献
15.
INTRODUCTION: Despite strong evidence regarding the role of CCND1 amplification and protein overexpression in breast carcinoma, the associations between CCND1 amplification/cyclin D1 overexpression and clinicopathological variables and clinical outcome remain controversial. AIMS OF THE STUDY: (1) to correlate cyclin D1 expression with gene amplification; (2) to analyse the correlations between CCND1 amplification and overexpression with clinicopathological features and patients' outcome in invasive breast cancer; (3) to define the prevalence and clinical significance of cyclin D1 overexpression and CCND1 amplification in ER positive breast carcinomas (4) to define the prevalence of cyclin D1 overexpression and CCND1 amplification in breast cancers with basal-like immunophenotype. MATERIALS AND METHODS: CCND1 amplification and protein expression were assessed on a tissue microarray containing 880 unselected invasive breast cancer cases, by means of chromogenic in situ hybridisation using the Spotlight CCND1 amplification probe and immunohistochemistry, using the rabbit monoclonal antibody SP4. RESULTS: A total of 59/613 tumours (9.6%) showed CCND1 amplification and 224/514 (43.6%) showed strong cyclin D1 expression. A strong positive correlation between CCND1 amplification and higher levels of cyclin D1 expression was found (P < 0.001). Basal-like cancers showed infrequent CCND1 amplification and cyclin D1 overexpression (P < 0.001). Both CCND1 amplification and cyclin D1 expression were associated with positive ER status. CCND1 gene amplification was an independent prognostic factor for patients with ER positive breast cancer. CONCLUSION: Our results demonstrate a strong correlation between CCND1 amplification and its protein expression in breast cancer. However, protein expression is more pervasive than gene amplification and associated with ER expression. 相似文献
17.
Introduction Changes in proliferation as measured by Ki67 occur within 14 days of starting treatment with an aromatase inhibitor and these
changes have been shown to be predictors of long term outcome. This study aimed to compare changes in proliferation following
14 days of treatment with anastrozole and letrozole. Methods Two hundred and six women with 209 estrogen receptor (ER) positive operable breast cancers (three bilateral) were randomly
allocated to receive either 14 days treatment with 2.5 mg of letrozole or 1 mg of anastrozole prior to surgery. Changes in
expression of estrogen (ER) and progesterone receptors (PgR) as assessed by ALLRED scores and proliferation as assessed by
Ki67 were analysed. The HER2 status of each tumour was also assessed using a combination of the Hercept test and FISH. Results Both letrozole and anastrozole reduced ER expression (ALLRED score) by a mean of 0.32 (0.20–0.44), P < 0.001 and PgR fell by a mean of 2.54 (2.20–2.89) P < 0.0001. Letrozole reduced proliferation from a geometric mean of 6.37% to 0.81%, P < 0.0001 and anastrozole reduced proliferation from 5.81% to 0.77%, P < 0.0001. There was no differences between drugs in the fall in ER, PgR or proliferation. Both letrozole and anastrozole
produced significant falls in proliferation in both HER2 positive and HER2 negative cancers, all P < 0.001. Discussion 14 days of both letrozole and anastrozole reduces proliferation, ER and PgR expression. No significant difference between
these two drugs was identified.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
18.
Based on molecular sub-classification, basal-like breast cancer is associated with aggressive behavior. These tumors are frequently
triple negative and lack traditional treatment targets. Angiogenesis, one of the hallmarks of cancer, is important for the
local growth and spread of malignant tumors and is now a treatment target. The aim of this study was to explore whether angiogenesis
is increased in relation to certain molecular subtypes of breast cancer with special focus on the basal-like category. Altogether,
we analyzed a total of 431 breast cancers from two independent series after dual immunohistochemical staining of Factor VIII
for endothelial cells and Ki-67 for proliferating cells. We then determined vascular proliferation in the most vascularized
areas of the tumor. In both Series I and II, high vascular proliferation index (VPI) was significantly associated with expression
of cytokeratin 5/6 ( P = 0.001, 0.010), P-cadherin ( P < 0.0005, <0.0005), epidermal growth factor receptor ( P = 0.003, 0.001), the basal-like subtype ( P = 0.001, 0.011), and the core basal phenotype ( P = 0.002, 0.002), respectively. In Series I, high VPI was associated with the triple negative phenotype ( P = 0.004) and p63 expression ( P = 0.008). Tumor angiogenesis, as measured by vascular proliferation, was increased in the basal-like subtype in two independent
breast cancer series and may thus be a possible treatment target in this category. Studies are required to evaluate whether
this novel angiogenesis marker can be used to stratify patients for anti-angiogenesis treatment. 相似文献
19.
Breast cancer mortality is frequently associated with metastatic disease. Metastasis models have shown adrenoceptor (AR) stimulation
induces cell migration which is inhibited by adrenoceptor antagonist drugs. We investigated adrenoceptor protein expression
in clinical breast tumours and its association with disease progression and prognosis. Immunohistochemistry on tissue microarrays
was used to characterise α1b, α2c and β 22 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical
outcome were statistically assessed. Strong α1b expression occurred in large high grade ( P < 0.0001), HER2+ ( P < 0.0001) or basal-like (CK5/6, P = 0.0005; CK14, P = 0.0001; EGFR, P = 0.003) cancers, showing increased proliferation (Mib1, P = 0.002), decreased apoptosis (Bcl2, P < 0.0001) and poor NPI membership ( P = 0.001). α1b expression correlated with poor cancer-specific survival (LR = 7.628, P = 0.022) and tumour recurrence (LR = 6.128, P = 0.047). Strong α2c was over-expressed in high grade ( P = 0.007), HER3+ ( P = 0.002) and HER4+ ( P < 0.0001) cancers with borderline increase in EGFR, p53 and MIB1 proteins, and inverse association with hormonal (PgR, P = 0.002) phenotype. In contrast, strong β 2 expression occurred in small-size, luminal-like (ER+, P < 0.001) tumours of low grade ( P < 0.001) and lymph node stage ( P = 0.027) that showed poor prognosis when hormonal treatment was withheld. Adrenoceptors were not found to be independent
predictors of clinical outcome. Alpha1b and α2c AR is over-expressed in basal-like breast tumours of poor prognosis. Strong
β 2 adrenoceptor expression is seen in patients with a luminal (ER+) tumour phenotype and good prognosis, due to benefits derived
from hormonal therapy. These findings suggest a possible role for targeted therapy using adrenoceptor antagonists. 相似文献
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