title: Surviving without oxygen: hypoxia regulation of mammary morphogenesis and anoikis.
abstract: Tumor hypoxia correlates with resistance to chemotherapy, increased incidence of metastasis and poor clinical prognosis. Early breast cancer lesions, such as carcinoma in situ, characterized by filled lumens, are often associated with hypoxic markers. However, the contribution of hypoxia to changes in tissue architecture in early pre-malignant lesions is not well defined. Using three-dimensional basement membrane cultures of mammary epithelial cells, we recently reported that acini-like structures exposed to hypoxia display epithelial disorganization and delayed lumen formation. We found that hypoxia, via HIF-1α, targets signaling pathways, specifically the Erk-Bim axis, to suppress anoikis-cell death in a 3D acinar model. Here, we discuss these findings further and present additional data, indicating that hypoxia-mediated alterations in acinar architecture and anoikis-associated Erk-Bim signaling are maintained in mammary epithelial cells after reoxygenation. Taken together, these findings may offer new insight into the contribution of hypoxia-mediated signaling in the progression of early breast cancer lesions and possible treatment of hypoxic cancers.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Whelan
authors.forename: Mauricio J
authors.initials: MJ
authors.lastname: Reginato
mesh_terms: D023102:Anoikis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D010100:Oxygen