Association of oestrogen receptor beta 2 (ERβ2/ERβcx) with outcome of adjuvant endocrine treatment for primary breast cancer – a retrospective study

<p>Abstract</p> <p>Background</p> <p>Oestrogen receptor beta (ERβ) modulates ERα activity; wild type ERβ (ERβ1) and its splice variants may therefore impact on hormone responsiveness of breast cancer. ERβ2/ERβcx acts as a dominant negative inhibitor of ERα and expression of ERβ2 mRNA has been proposed as a candidate marker for outcome in primary breast cancer following adjuvant endocrine therapy. We therefore now assess ERβ2 protein by immunostaining and mRNA by quantitative RT-PCR in relation to treatment outcome.</p> <p>Methods</p> <p>ERβ2-specific immunostaining was quantified in 141 primary breast cancer cases receiving adjuvant endocrine therapy, but no neoadjuvant therapy or adjuvant chemotherapy. The expression of mRNA for ERβ2/ERβcx was measured in 100 cases by quantitative RT-PCR. Statistical analysis of breast cancer relapse and breast cancer survival was performed using Kaplan Meier log-rank tests and Cox's univariate and multivariate survival analysis.</p> <p>Results</p> <p>High ERβ2 immunostaining (Allred score >5) and high ERβ2 mRNA levels were independently associated with significantly better outcome across the whole cohort, including both ERα positive and negative cases (Log-Rank P < 0.05). However, only ERβ2 mRNA levels were significantly associated with better outcome in the ERα + subgroup (Log-Rank P = 0.01) and this was independent of grade, size, nodal status and progesterone receptor status (Cox hazard ratio 0.31 P = 0.02 for relapse; 0.17 P = 0.01 for survival). High ERβ2 mRNA was also associated with better outcome in node negative cases (Log Rank P < 0.001).</p> <p>ERβ2 protein levels were greater in ERα positive cases (T-test P = 0.00001), possibly explaining the association with better outcome. Levels of ERβ2 protein did not correlate ERβ2 mRNA levels, but 34% of cases had both high mRNA and protein and had a significantly better outcome (Log-Rank relapse P < 0.005).</p> <p>Conclusion</p> <p>High ERβ2 protein levels were associated with ERα expression. Although most cases with high ERβ2 mRNA had strong ERβ2 immunostaining, mRNA levels but not protein levels were independently predictive of outcome in tamoxifen-treated ERα + tumours. Post-transcriptional control needs to be considered when assessing the biological or clinical importance of ERβ proteins.</p

A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have assessed the prevalence of germline mutations in <it>BRCA1 </it>and <it>BRCA2 </it>genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of <it>BRCA1-2 </it>mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of <it>BRCA1-2 </it>germline mutations was also evaluated.</p> <p>Methods</p> <p>Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for <it>BRCA1-2 </it>mutations by DHPLC analysis and DNA sequencing. Association of <it>BRCA1 </it>and <it>BRCA2 </it>mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.</p> <p>Results and Conclusion</p> <p>Overall, 8 <it>BRCA1 </it>and 5 <it>BRCA2 </it>deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in <it>BRCA2 </it>gene. The geographical distribution of <it>BRCA1-2 </it>mutations was related to three specific large areas of Sardinia, reflecting its ancient history: <it>a</it>) the Northern area, linguistically different from the rest of the island (where a <it>BRCA2 c.8764_8765delAG </it>mutation with founder effect was predominant); <it>b</it>) the Middle area, land of the ancient Sardinian population (where <it>BRCA2 </it>mutations are still more common than <it>BRCA1 </it>mutations); and <it>c</it>) the South-Western area, with many Phoenician and Carthaginian locations (where <it>BRCA1 </it>mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of <it>BRCA1-2 </it>germline mutations.</p

Tandem repeat distribution of gene transcripts in three plant families

Tandem repeats (microsatellites or SSRs) are molecular markers with great potential for plant genetic studies. Modern strategies include the transfer of these markers among widely studied and orphan species. In silico analyses allow for studying distribution patterns of microsatellites and predicting which motifs would be more amenable to interspecies transfer. Transcribed sequences (Unigene) from ten species of three plant families were surveyed for the occurrence of micro and minisatellites. Transcripts from different species displayed different rates of tandem repeat occurrence, ranging from 1.47% to 11.28%. Both similar and different patterns were found within and among plant families. The results also indicate a lack of association between genome size and tandem repeat fractions in expressed regions. The conservation of motifs among species and its implication on genome evolution and dynamics are discussed

Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer

INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. METHODS: Using immunohistochemical techniques, we focused on the expression and phosphorylation of hormone receptors themselves and examined the phosphorylation of ER-α Ser118 and ER-α Ser167 and the expression of ER-α, ER-β1, ER-βcx/β2, progesterone receptor (PR), PRA, and PRB in the primary breast carcinomas of 75 patients with metastatic breast cancer who received first-line treatment with endocrine therapy after relapse. RESULTS: Phosphorylation of ER-α Ser118, but not Ser167, was positively associated with overexpression of HER2, and HER2-positive tumors showed resistance to endocrine therapy. The present study has shown for the first time that phosphorylation of ER-α Ser167, but not Ser118, and expression of PRA and PRB, as well as ER-α and PR in primary breast tumors are predictive of response to endocrine therapy, whereas expression of ER-β1 and ER-βcx/β2 did not affect response to the therapy. In addition, patients with either high phosphorylation of ER-α Ser167, or high expression of ER-α, PR, PRA, or PRB had a significantly longer survival after relapse. CONCLUSION: These data suggest that phosphorylation of ER-α Ser167 is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in metastatic breast cancer

Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

In order to elucidate the relative importance of oestrogen receptor (ER)α, ERβ and an ERβ variant (ERβ2/βcx) in the response of breast cancers to tamoxifen, tumour levels of each receptor were assessed in 36 patients before and after 3 months of neoadjuvant treatment with tamoxifen (20 mg daily). All patients were postmenopausal women presenting with large ERα-positive breast cancers. Clinical response to treatment was assessed by tumour volume changes as determined from sequential ultrasounds and pathological response by comparison of the tumour morphology before and after treatment. Of 33 cases, 23 (70%) were classified as having a clinical response and 16 (48%) as having a response pathologically. All tumours stained positively for ERα and ERβ and 15 out of 33 (45%) for ERβ2/βcx. There were no significant differences in quantitative expression of any receptor between tumours that subsequently responded and that did not, whether response was assessed clinically or pathologically. Tamoxifen treatment was associated with a decrease in ERα, but an increase was the most frequent change (17 out of 33) in ERβ, and no consistent change was evident in staining of the ERβ2/βcx variant. In summary, ERβ1 and ERβ2/βcx variant protein are detected in ERα-positive breast tumours but their expression is not associated with a response to tamoxifen. Differential changes in ERα and ERβ were seen with treatment

Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis

<p>Abstract</p> <p>Background</p> <p>Central nervous system is a common site of metastasis in NSCLC and confers worse prognosis and quality of life. The aim of this prospective study was to evaluate the prognostic significance of clinical-pathological factors (CPF), serum CEA levels, and EGFR and HER2 tissue-expression in brain metastasis (BM) and overall survival (OS) in patients with advanced NSCLC.</p> <p>Methods</p> <p>In a prospective manner, we studied 293 patients with NSCLC in IIIB-IV clinical stage. They received standard chemotherapy. CEA was measured prior to treatment; EGFR and HER2 were evaluated by immunohistochemistry. BM development was confirmed by MRI in symptomatic patients.</p> <p>Results</p> <p>BM developed in 27, and 32% of patients at 1 and 2 years of diagnosis with adenocarcinoma (RR 5.2; 95% CI, 1.002–29; p = 0.05) and CEA ≥ 40 ng/mL (RR 11.4; 95% CI, 1.7–74; <it>p </it>< 0.01) as independent associated factors. EGFR and HER2 were not statistically significant. Masculine gender (RR 1.4; 95% CI, 1.002–1.9; <it>p </it>= 0.048), poor performance status (RR 1.8; 95% CI, 1.5–2.3; <it>p </it>= 0.002), advanced clinical stage (RR 1.44; 95% CI, 1.02–2; <it>p </it>= 0.04), CEA ≥ 40 ng/mL (RR 1.5; 95% CI, 1.09–2.2; <it>p </it>= 0.014) and EGFR expression (RR 1.6; 95% CI, 1.4–1.9; <it>p </it>= 0.012) were independent associated factors to worse OS.</p> <p>Conclusion</p> <p>High CEA serum level is a risk factor for BM development and is associated with poor prognosis in patients with advanced NSCLC. Surface expression of CEA in tumor cells could be the physiopathological mechanism for invasion to CNS.</p