VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis.

Authors:
Prof. Volker H Haase, M.D./Dr.med.
Prof. Volker H Haase, M.D./Dr.med.
Vanderbilt School of Medicine
Professor of Medicine, Cancer Biology and Molecular Physiology and Biophysics
Renal Medicine, Internal Medicine
Nashville, TN | United States
Prof. Volker Hans Haase, M.D. / Dr. med.
Prof. Volker Hans Haase, M.D. / Dr. med.
Vanderbilt University
Professor of Medicine, Cancer Biology and Molecular Physiology and Biophysics
Renal Medicine, Internal Medicine
Nashville, TN | United States

Am J Pathol 2010 May 9;176(5):2269-82. Epub 2010 Apr 9.

Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Overexpression of hypoxia inducible factor-1 (HIF-1)alpha, which is common in most solid tumors, correlates with poor prognosis and high metastatic risk in breast cancer patients. Because HIF-1alpha protein stability is tightly controlled by the tumor suppressor von Hippel-Lindau (VHL), deletion of VHL results in constitutive HIF-1alpha expression. To determine whether VHL plays a role in normal mammary gland development, and if HIF-1alpha overexpression is sufficient to initiate breast cancer, Vhl was conditionally deleted in the mammary epithelium using the Cre/loxP system. During first pregnancy, loss of Vhl resulted in decreased mammary epithelial cell proliferation and impaired alveolar differentiation; despite these phenotypes, lactation was sufficient to support pup growth. In contrast, in multiparous dams, Vhl(-/-) mammary glands exhibited a progressive loss of alveolar epithelium, culminating in lactation failure. Deletion of Vhl in the epithelium also impacted the mammary stroma, as there was increased microvessel density accompanied by hemorrhage and increased immune cell infiltration. However, deletion of Vhl was not sufficient to induce mammary tumorigenesis in dams bred continuously for up to 24 months of age. Moreover, co-deletion of Hif1a could not rescue the Vhl(-/-)-dependent phenotype as dams were unable to successfully lactate during the first lactation. These results suggest that additional VHL-regulated genes besides HIF1A function to maintain the proliferative and regenerative potential of the breast epithelium.

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Source
http://dx.doi.org/10.2353/ajpath.2010.090310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861092PMC
May 2010
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