losartan-potassium and Carcinoma--Ductal--Breast

Erythropoietin (EPO) was shown to reduce tumor survival in recent trials, however, its mechanisms of action are unclear. Efforts to measure tumor EPO receptor (EPOR) are limited by the promiscuity of EPOR antibodies, and concerns as to whether EPOR mRNA measurements are confounded by heterogeneity of tumor vasculature, a known EPOR source.. This study compared mRNA levels of EPOR and JAK2 in 11 breast tumor epithelial versus endothelial dissections.. In nine tumors EPOR mRNA was 2.6 (1.2-5.7)-fold lower in the epithelial fraction, however, this reduction was less than the reduction of endothelial markers. In two tumors, EPOR mRNA was 2.9 (1.7-4.0)-fold higher in the epithelial fraction. The inter-tumor variation in EPOR levels exceeded the intra-tumor variation between fractions. Similar results were obtained for JAK2.. Tumor vasculature is not the sole source of EPOR and JAK2, and tumors can be segregated by EPOR and JAK2 levels for correlative analysis with clinical outcomes.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Endothelium, Vascular; Epithelial Cells; Erythropoietin; Female; Humans; Janus Kinase 2; Lasers; Microdissection; Middle Aged; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stromal Cells

STAT3 contributes to increase of EPO expression which is also HIF-1 dependent. EPO receptor activates STAT3. Expressions of STAT3 and hypoxia induced proteins: HIF-1, EPO and EPOR show mutual correlations in primary ductal breast cancers, which suggest co-operation among these proteins. Moreover, EPO-EPOR signaling was reported to mediate cell survival by targeting Bcl-xL in competition with Bax-dependent apoptosis. Our present study was focused on immunohistochemical evaluation of STAT3, HIF-1alpha, EPO and EPOR in relation to apoptosis regulators, Bax and Bcl-xL in 39 metastases of ductal breast cancers to lymph nodes. The proteins were abundantly expressed by cancer cells. HIF-1alpha correlated with EPOR in all and in chemotherapy treated metastases (r=0.428, p=0.007 and r=0.462, p=0.040, respectively). HIF-1 associated significantly with EPO in chemotherapy spared metastases (r=0.549, p=0.015) and comparison between those proteins almost reached statistical significance in entire number of metastatic breast cancers (r=0.309, p=0.056). Metastases from T2 primary tumors had significantly higher expressions of HIF-1alpha, EPO and EPOR compared to T1 originating metastases (p=0.020, p=0.028, p=0.021, respectively). Bax correlated with EPO and EPOR in all studied nodal metastases (r=0.449, p=0.006 and r=0.421, p=0.011, respectively) and so did Bcl-xL with HIF-1alpha (r=0.440, p=0.007), EPO and EPOR (r=0.383, p=0.021, r=0.495, p=0.002, respectively). Metastatic breast cancers seem to be areas of intensive signaling by STAT3, HIF-1, EPO and EPOR. Strong Bax and Bcl-xL labeling reflects accelerated cell turnover in nodal metastases. By means of association with Bcl-xL, HIF-1alpha, EPO and EPOR could favor growth of nodal metastases and survival of breast cancers cells.

Topics: bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Carcinoma, Ductal, Breast; Erythropoietin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Lymphatic Metastasis; Receptors, Erythropoietin; STAT3 Transcription Factor

STAT3 upregulates expression of HIF-1 induced EPO. Receptor EPOR was reported to activate STAT3. Our study was aimed at demonstration of tissue immunoreactivities of those proteins and determination of their relationships in reference to clinicopathological variables of breast cancers. We detected STAT3, HIF-1alpha, EPO and EPOR in specimens of 76 human, female, ductal breast cancers by immunohistochemistry. STAT3 was detected in 38 of 76 cancers (50%). HIF-1alpha was found in 55 cases (72%). EPO positive tumors comprised 89% of all the cancers (68 cases). EPOR was also visualized in 55 cases (72%). Anti-HIF-1alpha and anti-STAT3 stained nuclei and cytoplasm of breast cancer cells in diffuse and finely granular fashion. Strong membranous expressions of EPO and EPOR were distributed in cytoplasmic and membranous granularity or diffuse staining. STAT3 correlated with HIF-1 in general (r=0.4012, p<0.0001) and in different patients' subgroups. STAT3 was significantly associated with EPO and EPOR in all the cancers (r=0.2370, p=0.039 and r=0.3336, p=0.003, respectively). Besides a correlation between STAT3 and EPOR in node negative ones, STAT3 wasn't related to EPO and EPOR in remaining subgroups. HIF-1alpha correlated with EPO and EPOR in most of analyzed groups. Immunoreactivity to EPO generally was associated with EPOR (r=0.3520, p=0.002). Statistically analyzed distributions of the proteins reflected functional dependences among STAT3, HIF-1alpha, EPO and EPOR in cellular signal conduction.

Topics: Breast Neoplasms; Carcinoma, Ductal, Breast; Erythropoietin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Receptors, Erythropoietin; Signal Transduction; STAT3 Transcription Factor

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Recombinant Proteins; Treatment Outcome