title: The role of tumor hypoxia in MUC1-positive breast carcinomas.
abstract: Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell-cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1α) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1α and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1α (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-κB (IκBα), driving NF-κB to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-κB expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-κB to the nucleus. Our data also support the notion that activation of HIF-1α in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.
authors: Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil.
authors: Juliana Silva
authors: JS
authors: Zanetti
authors: Danilo Fiqueredo
authors: DF
authors: Soave
authors: João Paulo
authors: JP
authors: Oliveira-Costa
authors: Giórgia Gobbi
authors: GG
authors: da Silveira
authors: Leandra Náira Zambelli
authors: LN
authors: Ramalho
authors: Sérgio Britto
authors: SB
authors: Garcia
authors: Sérgio
authors: S
authors: Zucoloto
authors: Alfredo
authors: A
authors: Ribeiro-Silva
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D018396:Mucin-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C060192:MUC1 protein, human; D018396:Mucin-1; D016328:NF-kappa B; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A