title: STAT3 and hypoxia induced proteins--HIF-1alpha, EPO and EPOR in relation with Bax and Bcl-xL in nodal metastases of ductal breast cancers.
abstract: 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.
authors.affiliation: Department of Medical, Collegium Pathologicum, Medical University of Bialystok, Waszyngtona St 13, 15-269 Bialystok, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wincewicz
authors.forename: Mariusz
authors.initials: M
authors.lastname: Koda
authors.forename: Mariola
authors.initials: M
authors.lastname: Sulkowska
authors.forename: Luiza
authors.initials: L
authors.lastname: Kanczuga-Koda
authors.forename: Dominik
authors.initials: D
authors.lastname: Wincewicz
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Sulkowski
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C494811:BCL2L1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D004921:Erythropoietin