Surviving without oxygen: Hypoxia regulation of mammary morphogenesis and anoikis

Whelan, Kelly A.; Reginato, Mauricio J.

doi:10.4161/cc.10.14.16532

Cited by 12 publications

(10 citation statements)

References 49 publications

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“…As mentioned above, in addition to being regulated by hypoxia, HIF-1α stability has been shown to be regulated by other stimuli, including nitric oxide, reactive oxygen species, nutrient stress, and glycolytic intermediates [10,21-23]. Furthermore, several studies have shown that hypoxia causes mammary epithelial disorganization and induces a cancer cell-like phenotype in human MECs [128-130]. Thus, to link an effect of hypoxia to mammary development and lactation, it is essential to quantitatively measure oxygen tension changes in the mammary gland from pregnancy to lactation.…”

Section: Resultsmentioning

confidence: 99%

Emerging evidence of the physiological role of hypoxia in mammary development and lactation

Shao

Zhao

2014

J Animal Sci Biotechnol

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Hypoxia is a physiological or pathological condition of a deficiency of oxygen supply in the body as a whole or within a tissue. During hypoxia, tissues undergo a series of physiological responses to defend themselves against a low oxygen supply, including increased angiogenesis, erythropoiesis, and glucose uptake. The effects of hypoxia are mainly mediated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimeric transcription factor consisting of α and β subunits. HIF-1β is constantly expressed, whereas HIF-1α is degraded under normal oxygen conditions. Hypoxia stabilizes HIF-1α and the HIF complex, and HIF then translocates into the nucleus to initiate the expression of target genes. Hypoxia has been extensively studied for its role in promoting tumor progression, and emerging evidence also indicates that hypoxia may play important roles in physiological processes, including mammary development and lactation. The mammary gland exhibits an increasing metabolic rate from pregnancy to lactation to support mammary growth, lactogenesis, and lactation. This process requires increasing amounts of oxygen consumption and results in localized chronic hypoxia as confirmed by the binding of the hypoxia marker pimonidazole HCl in mouse mammary gland. We hypothesized that this hypoxic condition promotes mammary development and lactation, a hypothesis that is supported by the following several lines of evidence: i) Mice with an HIF-1α deletion selective for the mammary gland have impaired mammary differentiation and lipid secretion, resulting in lactation failure and striking changes in milk compositions; ii) We recently observed that hypoxia significantly induces HIF-1α-dependent glucose uptake and GLUT1 expression in mammary epithelial cells, which may be responsible for the dramatic increases in glucose uptake and GLUT1 expression in the mammary gland during the transition period from late pregnancy to early lactation; and iii) Hypoxia and HIF-1α increase the phosphorylation of signal transducers and activators of transcription 5a (STAT5a) in mammary epithelial cells, whereas STAT5 phosphorylation plays important roles in the regulation of milk protein gene expression and mammary development. Based on these observations, hypoxia effects emerge as a new frontier for studying the regulation of mammary development and lactation.

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Section: Resultsmentioning

confidence: 99%

Emerging evidence of the physiological role of hypoxia in mammary development and lactation

Shao

Zhao

2014

J Animal Sci Biotechnol

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“…However, the role of HIF-1 in ERBB2-mediated oncogenesis is not known. We have recently shown that exposure to hypoxia suppresses anoikis in mammary epithelial cells in a manner that is dependent upon HIF-1␣ expression leading to inhibition of luminal clearance and development of disorganized acinar structures (14,15). Furthermore, HIF-1, like ERBB2, acts at the ERK-BIM axis to promote cell survival in the absence of adhesion (14).…”

Section: Adhesion To Extracellular Matrix (Ecm)mentioning

confidence: 99%

The Oncogene HER2/neu (ERBB2) Requires the Hypoxia-inducible Factor HIF-1 for Mammary Tumor Growth and Anoikis Resistance

Whelan¹,

Schwab

Karakashev³

et al. 2013

Journal of Biological Chemistry

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“…Intermittent hypoxia, also referred to as cycling hypoxia, is characterized by cyclic periods of hypoxia and reoxygenation and plays the main role in resistance of solid tumor treatments (Figure 3) [23–26]. Hypoxic microenvironments are characterized by extreme heterogeneities in tumor cells oxygenation that arise as a result of the increased oxygen diffusion distance due to tumor expansion and poorly developed vascular networks [22, 27]. Gradients in oxygen are frequently found surrounding perfused vessels, ranging from normal values near the blood vessel to complete anoxia adjacent to necrosis [27, 28].…”

Section: Ros and Hypoxia In Solid Tumorsmentioning

confidence: 99%

“…Hypoxic microenvironments are characterized by extreme heterogeneities in tumor cells oxygenation that arise as a result of the increased oxygen diffusion distance due to tumor expansion and poorly developed vascular networks [22, 27]. Gradients in oxygen are frequently found surrounding perfused vessels, ranging from normal values near the blood vessel to complete anoxia adjacent to necrosis [27, 28]. The balanced proportion of hypoxic cells in cancer is driven by the tolerance of individual cells to these different types of hypoxia and varies remarkably among different tumors with otherwise similar clinical features [29].…”

Section: Ros and Hypoxia In Solid Tumorsmentioning

confidence: 99%

A Paradoxical Chemoresistance and Tumor Suppressive Role of Antioxidant in Solid Cancer Cells: A Strange Case of Dr. Jekyll and Mr. Hyde

Kwee

2014

BioMed Research International

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Modulation of intracellular antioxidant concentration is a double-edged sword, with both sides exploited for potential therapeutic benefits. While antioxidants may hamper the efficacy of chemotherapy by scavenging reactive oxygen species and free radicals, it is also possible that antioxidants alleviate unwanted chemotherapy-induced toxicity, thus allowing for increased chemotherapy doses. Under normoxic environment, antioxidants neutralize toxic oxidants, such as reactive oxygen species (ROS), maintaining them within narrow boundaries level. This redox balance is achieved by various scavenging systems such as enzymatic system (e.g., superoxide dismutases, catalase, and peroxiredoxins), nonenzymatic systems (e.g., glutathione, cysteine, and thioredoxin), and metal-binding proteins (e.g., ferritin, metallothionein, and ceruloplasmin) that sequester prooxidant metals inhibiting their participation in redox reactions. On the other hand, therapeutic strategies that promote oxidative stress and eventually tumor cells apoptosis have been explored based on availability of chemotherapy agents that inhibit ROS-scavenging systems. These contradictory assertions suggest that antioxidant supplementation during chemotherapy treatment can have varied outcomes depending on the tumor cellular context. Therefore, understanding the antioxidant-driven molecular pathways might be crucial to design new therapeutic strategies to fight cancer progression.

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Surviving without oxygen: Hypoxia regulation of mammary morphogenesis and anoikis

Cited by 12 publications

References 49 publications

Emerging evidence of the physiological role of hypoxia in mammary development and lactation

Emerging evidence of the physiological role of hypoxia in mammary development and lactation

The Oncogene HER2/neu (ERBB2) Requires the Hypoxia-inducible Factor HIF-1 for Mammary Tumor Growth and Anoikis Resistance

A Paradoxical Chemoresistance and Tumor Suppressive Role of Antioxidant in Solid Cancer Cells: A Strange Case of Dr. Jekyll and Mr. Hyde

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