osteoprotegerin and Carcinoma--Ductal--Breast

Searching for sensitive, minimally invasive biomarkers that represent tumor-associated changes in the peripheral blood might enable the early diagnosis of breast cancer (BC) and monitoring of tumor progression.. Herein, we investigated the association of some circulating biomarkers with the risk of metastasis. In the current study, 115 BC patients which were subdivided into two groups: nonmetastatic breast cancer patients (NMBC) (n=83) and metastatic breast cancer patients (MBC) (n=32), and 79 apparently healthy controls were recruited. Serum protein levels of lysosomal protein transmembrane 4 beta (LAPTM4B), receptor activator of nuclear factor-kappa b (NF-Kb) ligand (RANKL), osteoprotegerin (OPG), vitamin D (VIT D), chitinase-3-like protein 1 (also known as YKL-40), and sirtuin 1 (SIRT1) were assessed in blood samples using ELISA technique.. The results showed that RANKL and OPG had the highest diagnostic potential for MBC detection, with area under the curve values of 0.97 and 0.94, respectively. Moreover, logistic regression analysis showed that RANKL had the highest differentiation power in the discrimination of MBC from NMBC.. The study highlighted that measuring RANKL and OPG may be helpful in the early detection of metastasis in Egyptian patients with BC.

Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Case-Control Studies; Egypt; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Osteoprotegerin; Prognosis; RANK Ligand; ROC Curve; Young Adult

Genetic susceptibility for breast cancer (BC) is still poorly understood. A combination of multiple low-penetrant alleles of cancer-related genes and gene-gene interactions (epistasis) contributes to BC risk. Genetic variants in receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), chitinase-3-like protein 1 (CHI3L1), and vitamin D receptor (VDR) genes are implicated in breast carcinogenesis; however, the influence of their epistatic effects on BC susceptibility has not yet been studied. We investigated the association of single nucleotide polymorphism (SNP)-SNP interactions and haplotypes of 6 SNPs in these 4 genes with the genetic predisposition of BC in Egyptian women.. Data of 115 BC patients and 120 cancer-free controls were studied. Association tests were conducted using logistic regression models.. Individual SNPs showed weak statistical significance with BC susceptibility. The interactions between RANKL-rs9533156 and OPG-rs2073618; OPG-rs2073618 with CHI3L1-rs4950928, VDR-rs2228570 and VDR-rs1544410; OPG-rs2073617 and VDR-rs1544410; VDR-rs2228570 and VDR-rs1544410 were strongly associated with increased BC risk after adjustment for multiple comparisons. No SNPs were in strong linkage disequilibrium. The TCTCTG-rs9533156-rs2073618-rs2073617-rs4950928-rs2228570-rs1544410 haplotype was significantly associated with increased BC risk (adjusted odds ratio = 8.33; 95% confidence interval, 1.32-52.46; P = .025) compared with controls. TCCCTG haplotype stratified BC patients according to estrogen receptor/progesterone receptor status. TCTCTA was positively associated, and TCTCTG and TGTCTG haplotypes inversely correlated with bone metastasis. Bioinformatic analysis revealed 13 proteins commonly interacting with our 4 genes; the most significant was signal transducer and activator of transcription 5B.. Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR genes via gene-gene interaction may help predict BC risk and prognosis.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Case-Control Studies; Chitinase-3-Like Protein 1; Egypt; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Lymphatic Metastasis; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; Prognosis; RANK Ligand; Receptors, Calcitriol; Retrospective Studies; Risk Factors

Patients with locally advanced breast cancer treated with neoadjuvant chemotherapy are at risk of cancer treatment-induced bone loss and consequently of increased skeletal morbidity. In addition, this situation could be worsened by the fact that only a minority of patients with breast cancer have sufficient vitamin D. A comprehensive evaluation of bone homeostasis is critical in this context. We retrospectively evaluated the serum levels of calcium, vitamin D, TRAIL, RANK ligand (RANKL), Osteoprotegerin (OPG), Bone TRAP, CrossLaps and DKK1 in 77 patients (median age: 50 years; range 25-74), with locally advanced breast cancer treated in our institute with anthracyclines-taxane neoadjuvant chemotherapy (7 cycles of 21 days/each) between March 2007 and August 2008. Serum samples were collected before the first (baseline) and the last treatment cycle. Variations and correlations between biomarker levels were evaluated. At baseline, 79.5 % of patients had vitamin D insufficiency (<30 ng/ml), increasing to 97.4 % at the end of the neoadjuvant chemotherapy (p < 0.0001). Calcium and RANKL serum concentrations were also significantly decreased, while OPG was significantly increased, resulting in lower RANKL/OPG ratio. Calcium and vitamin D, RANKL and vitamin D and RANKL and OPG levels were significantly correlated (Spearman's coefficient r = 0.2721, p = 0.0006; r = 0.1916, p = 0.002; and r = -0.179, p = 0.03, respectively). Nearly all included patients suffered from vitamin D insufficiency by the end of the neoadjuvant chemotherapy with changes in the calcium/RANKL/OPG axis that are evocative of deregulation of a functional regulatory mechanism. Further studies are needed to determine how drugs modulate this regulatory mechanism to preserve bone homeostasis in patients with breast cancer.

Topics: Acid Phosphatase; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone and Bones; Breast Neoplasms; Calcium; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Collagen; Cyclophosphamide; Docetaxel; Epirubicin; Female; Fluorouracil; Humans; Intercellular Signaling Peptides and Proteins; Isoenzymes; Middle Aged; Neoadjuvant Therapy; Osteoprotegerin; Peptide Fragments; Prevalence; RANK Ligand; Retrospective Studies; Statistics, Nonparametric; Tartrate-Resistant Acid Phosphatase; Taxoids; TNF-Related Apoptosis-Inducing Ligand; Vitamin D; Vitamin D Deficiency

Osteoprotegerin (OPG) is involved in the regulation of bone turnover through binding to the receptor activator of nuclear factor kappaB ligand (RANKL), and has also been reported to be a potential survival factor for several different cell types. The survival effects are mediated through inhibition of the activity of tumour necrosis factor related apoptosis inducing ligand (TRAIL). Both breast and prostate cancer cells produce sufficient amounts of OPG to be protected against the effects of TRAIL in vitro.. To investigate the spatial expression of OPG, RANKL, and TRAIL in non-neoplastic breast tissue and breast cancer, and its relation with oestrogen receptor (ER) expression.. Forty breast cancers (20 ER+, 20 ER-) and five non-neoplastic breast tissue samples were stained with antibodies against OPG, RANKL, and TRAIL.. OPG was not expressed in non-neoplastic breast tissue except when colocalised with altered columnar epithelium. RANKL was expressed at the apical surface of luminal epithelial cells and TRAIL was expressed in myoepithelial cells. All three proteins were expressed in some breast cancers but showed no significant association with tumour type. OPG expression showed a significant positive correlation with ER expression (p = 0.011).. This is the first published study of the spatial expression of OPG, RANKL, and TRAIL in breast tissue and breast cancer. The localisation of each protein was specific and they were not colocalised. This specificity may provide a useful marker of functional differentiation in breast cancer; for example, TRAIL expression as a marker of myoepithelial differentiation.

Topics: Apoptosis Regulatory Proteins; Biomarkers, Tumor; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Carrier Proteins; Female; Glycoproteins; Humans; Membrane Glycoproteins; Neoplasm Invasiveness; Neoplasm Proteins; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Receptors, Progesterone; Receptors, Tumor Necrosis Factor; Retrospective Studies; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

During normal bone remodeling, the receptor activator of nuclear factor-kappaB (RANK) interacts with its ligand RANKL, which is present on pre-osteoclasts, resulting in bone resorption and initiation of new bone formation. When breast cancer metastasizes to bone, normal bone remodeling is disturbed by invasion of tumor cells, resulting in osteolytic lesions. We have studied the expression of both RANK and RANKL in 10 nonneoplastic breast samples, 58 infiltrating ductal carcinoma (IDC), and 43 breast cancer bony metastases (BTM). RANK seemed to be present in all samples tested. However, whereas RANKL expression was observed in 90% of nonneoplastic breast, RANKL expression was only observed in 62% of nonmetastatic IDC, 31% of metastatic IDC, and 2% of osteolytic BTM lesions. This decreased or absent expression of RANKL in the tumor cells may allow RANK, which is normally expressed as a receptor on the cell surface, to target RANKL present on the cell surface of normal osteoblasts and stromal cells of the bone. Stimulation of the normal osteoblasts and stromal cells by the tumor cells may then lead to secondary osteoclastogenesis, resulting in the osteolytic phenotype common to breast metastases.

Topics: Bone and Bones; Bone Remodeling; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Immunohistochemistry; Neoplasm Metastasis; Osteoblasts; Osteoclasts; Osteoprotegerin; Phenotype; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Time Factors