The G protein-coupled oestrogen receptor 1 (GPER-1) is a potential prognostic marker in breast cancer. However, its role in male breast cancer (MBC) is still unknown. This study evaluates the ...expression of GPER-1 in MBC samples and correlates these data with clinical and pathological parameters including patients' survival.
For this retrospective analysis of a prospectively maintained cohort of patients with MBC, we examined 161 specimens for GPER-1 expression using immunohistochemistry. An immunoreactive score (IRS) was calculated based on staining intensity and the percentage of positive tumour cells. Then, we correlated GPER-1 IRS with clinical and pathological parameters, and overall and relapse-free survival.
About 40% of MBC samples were positive for GPER-1 expression (IRS ≥ 4). There was no significant correlation with clinicopathological parameters, such as hormone receptor status or grading. However, a statistical trend was observed for tumour size (≥ 2 cm,
= 0.093). Kaplan-Meier survival analysis revealed no significant correlation with relapse-free survival. However, there was a significant correlation with overall survival, but when we adjusted the log-rank
-value to compensate for the cut-off point optimization method, it rose above 0.1. Additionally, GPER-1-positive patients were older at diagnosis. When adjusted for age by multivariable Cox regression analysis, the significance of GPER-1 status for survival was further reduced.
We found no significant prognostic value of GPER-1 in this MBC cohort as anticipated from studies on female BC. Future studies with higher sample size are needed to further verify a potential sex-specific role of GPER-1.
Purpose
To evaluate the pattern of recurrence of breast cancer according to its biological subtype in a large cohort of patients treated with therapy representative of current practice.
Patients and ...methods
Patients treated between 2000 and 2016 with known biological subtype were eligible. Data were prospectively collected. Primary endpoint was the subtype-dependent pattern and time of recurrence. Loco-regional and distant site and time of recurrence were assessed.
Results
Median follow-up time was 80.8 months. For 12,053 (82.5%) of 14,595 patients with primary non-metastatic invasive breast cancer a subtype classification was possible. The luminal A subtype had the highest 10-year survival followed by luminal B and luminal/HER2. The worst survival demonstrated HER2 enriched and TNBC. HER2 and TNBC had the highest rate of recurrence in the first 5 years, whereas the rate of recurrence for luminal A and luminal B tumors was initially low, but remained continuously even after 10 years of follow-up. Luminal A tumors demonstrated the lowest rate of distant metastases predominantly in bone. So did luminal B tumors. HER2 enriched subtype was characterized with increased rate of loco-regional recurrence and distant metastases in bone, liver and brain. Luminal/HER2 had pattern of relapse similar to HER2 enriched tumors, with exception of loco-regional relapse and brain metastases. TNBC had higher rate of lung, bone and brain metastases as well as loco-regional relapse.
Conclusion
Breast cancer subtypes are associated with different time and pattern of recurrence and it should be considered during treatment decision.
Loss of HER2 after HER2-targeted treatment Ignatov, Tanja; Gorbunow, Franceska; Eggemann, Holm ...
Breast cancer research and treatment,
06/2019, Letnik:
175, Številka:
2
Journal Article
Recenzirano
Purpose
HER2 expression has been reported to be discordant between primary tumor and metastatic tissue.
Patients and methods
HER2 discordance and relation to HER2-targeted treatment was investigated ...in 227 patients with primary breast cancer.
Results
HER2 discordance between primary biopsy and second biopsy after neoadjuvant or adjuvant treatment was observed in 20.7%. This discordance was related only to the use of HER2-targeted treatment: 30 of 33 (90.9%) women with downgraded HER2 expression underwent a HER2-targeted therapy, whereas in the group of patients with concordant HER2 expression, only 32 of 180 (17.8%) received HER2-targeted treatment (
p
< 0.0001). HER2 discordance was associated with reduced disease-free survival but not overall survival. In a second cohort, including patients with HER2 overexpressing tumors, trastuzumab treatment was associated with change of HER2 expression from positive to negative in 47.3% of cases. Addition of pertuzumab increased the rate of HER2 loss up to 63.2%. Notably, the interval between last HER2-targeted treatment and the time of surgical excision of the tumor after neoadjuvant chemotherapy (NACT) or the biopsy of the metachronous metastasis was associated with a significant change in HER2 expression. The median time between NACT and the time of surgical excision was 23 days (range 5–81 days) for tumors with decreased HER2 expression and 51 days (range 10–179 days) for tumors with concordant HER2 expression. Furthermore, median time between the end of adjuvant treatment and second histology of the metachronous metastases accounted for 15 days (range 2–165 days) and 478 days (range 7–2739 days) was observed in the group of patients with decreased or unchanged HER2 expression, respectively.
Conclusion
The interval between anti-HER2 treatment and the determination of HER2 in second histology is strongly associated with HER2 expression.
The neuropeptide head activator (HA) is a mitogen for mammalian cell lines of neuronal or neuroendocrine origin. HA signalling is mediated by a G-protein-coupled receptor (GPCR). Orphan GPCRs with ...homology to peptide receptors were screened for HA interaction. Electrophysiological recordings in frog oocytes and in mammalian cell lines as well as Ca(2+) mobilisation assays revealed nanomolar affinities of HA to GPR37. HA signal transduction through GPR37 was mediated by an inhibitory G protein and required Ca(2+) influx through a channel of the transient receptor potential (TRP) family. It also required activation of Ca(2+)-dependent calmodulin kinase and phosphoinositide 3-kinase. Respective inhibitors blocked HA signalling and HA-induced mitosis in GPR37-expressing cells. HA treatment resulted in internalisation of GPR37. Overexpression of GPR37 led to aggregate formation, retention of the receptor in the cytoplasm and low survival rates of transfected cells, confirming the notion that misfolded GPR37 contributes to cell death, as observed in Parkinson's disease.
Background
The role of G-protein-coupled estrogen receptor 1 (GPER-1) in the development of tamoxifen resistance in breast cancer is a highly controversial issue. The aim of this study was to ...determine the expression of GPER-1 in the clinical routine under conditions of endocrine treatment.
Patients and methods
GPER-1 expression was analyzed in 442 patients with primary invasive breast cancer. GPER-1 score of > 3 was determined as positive. Expression data were correlated with clinical and pathological characteristics and patient survival.
Results
GPER-1 expression was observed in 352 (80.9%) cases, and positively correlated with estrogen and progesterone receptor status (
p
= 0.0001). GPER-1 positivity was associated with an increased grade of differentiation (
p
= 0.0001) and with a low level of Ki-67 expression (
p
= 0.0001). High GPER-1 expression was associated with a decreased level upon systemic treatment (
p
= 0.011). In the whole cohort, GPER-1 expression was associated with prolonged disease-free survival (DFS). DFS between tamoxifen- and aromatase inhibitor-treated GPER-1-positive patients was similar (
p
= 0.090). Notably, after matching the analysis for the most important prognostic factors, DFS for tamoxifen-treated GPER-1-positive patients was 69.1%, which is a percentage that is significantly lower compared to DFS for GPER-1-positive patients treated with aromatase inhibitors (92.7%) (
p
= 0.005).
Conclusion
GPER-1 expression is a favorable prognostic factor in breast cancer patients. Its predictive role for poor benefit form tamoxifen treatment should be investigated in further studies.
AbstractBackgroundThe relationship between nodal micrometastases and clinical outcome of endometrial cancer is unclear. Patients and methodsWe performed a multicenter, retrospective registry-based ...study of 2392 patients with endometrial cancer with and without nodal micrometastases. The primary outcome measure was disease-free survival. ResultsAfter exclusions, the final study involved 428 patients: 302 (70.6%) with node-negative endometrial cancer, who did not receive adjuvant treatment, 95 (22.2%) with nodal micrometastases who received adjuvant treatment, and 31 (7.2%) with nodal micrometastases who did not receive adjuvant treatment. The median follow-up was 84.8 months. Without adjuvant therapy the disease-free survival in the cohort of patients with micrometastases was significantly reduced as compared with disease-free survival in the node-negative cohort ( p = 0.0001). With adjuvant therapy the median disease-free survival of patients with nodal micrometastases was similar with those of node-negative patients ( p = 0.648). The adjusted hazard ratio for disease events among patients with micrometastases and no adjuvant therapy, as compared with node-negative patients, was 2.23 (95% confidence interval CI 1.26–3.95). In the cohort with micrometastases the relative risk of events was significantly decreased by adjuvant therapy (HR 0.29, 95%CI 0.13–0.65) even after adjustment for age at diagnosis, myometrial invasion, histological grade and type, and performance status. ConclusionsNodal micrometastases are associated with decreased disease-free survival of patients with endometrial cancer. Adjuvant therapy was associated with improved disease-free survival of patients with micrometastases.
Lysophospholipids are bioactive molecules influencing numerous cellular processes such as proliferation, differentiation, and motility. As extracellular ligands, they interact with specific members ...of the G-protein-coupled receptor family. We show in this paper that the lysophospholipid sphingosylphosphorylcholine is a high-affinity ligand for the orphan G-protein-coupled receptor GPR12. Heterologous expression of GPR12 in Chinese hamster ovary cells and in frog oocytes revealed a high-affinity interaction with sphingosylphosphorylcholine in the nanomolar range. Blockade of its action by pertussis toxin was taken as evidence that GPR12 is coupled to an inhibitory G-protein. In the adult mouse brain, GPR12 was expressed in the limbic system. During mouse embryonal development, GPR12 transcripts were detected in the CNS, especially in areas where neuronal differentiation occurs. Consistent with this we found that cultures of embryonal cerebral cortical neurons responded to sphingosylphosphorylcholine with an increase in synaptic contacts. The GPR12-expressing hippocampal cell line HT22 reacted to sphingosylphophorylcholine with an increase in cell proliferation and cell clustering. Other receptors known to interact at nanomolar concentrations with sphingosylphosphorycholine were expressed neither in the developing cerebral cortex nor in the HT22 cell line. We therefore hypothesize that sphingosylphosphorylcholine, most likely by interaction with GPR12, has positive effects on the differentiation and maturation of postmitotic neurons and that it may also influence the proliferation of neuronal precursor cells.
We identified and cloned the mouse orthologue of human GPR6 as a new member of the lysophospholipid-receptor family. Sphingosine-1-phosphate (S1P) activated GPR6, transiently expressed in frog ...oocytes or in Chinese hamster ovary (CHO) cells, with high specificity and nanomolar affinity. The GPR6 gene was found to be located on chromosome 10B1 and a single exon coded for the entire open-reading frame. Signal transduction of S1P was inhibited by pertussis toxin, suggesting a coupling of GPR6 to an inhibitory G protein. In CHO cells transfected with GPR6, the sphingosine-kinase pathway mediated Ca(2+) mobilization from internal stores. Apoptotic cell death was induced by serum deprivation or H(2)O(2) treatment and was prevented by S1P in GPR6-, but not in vector-transfected CHO cells. The antiapoptotic effect of S1P required activation of sphingosine kinase and was accompanied by an increase in MAP-kinase phosphorylation.
Exposure to higher levels of steroid hormones, like that in pregnancy or during combined hormonal contraception, increases the risk of venous thromboembolism. Development of resistance to activated ...protein C (APC) thought to be the underlying pathomechanism of this prothrombotic state. This coagulation phenomena is largely to be explained by the hormone-induced impairment of the protein S/ tissue factor pathway inhibitor (TFPI) leading to a less efficient inactivation of factor Va and factor VIIIa by APC. APC resistance and decreased protein S/TFPI function were associated with the risk of first as well as recurrent venous thromboembolism. Preexisting disturbances in these pathways are likely to predispose to thrombosis during hormone exposure and can persist over years after the thrombosis event.Further studies are necessary to investigate the predictive value of forgoing APC resistance and decreased protein S/TFPI function or an excessive alteration in these parameters during hormone intake on the development of hormone-induced venous thromboembolism.
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