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

Tiffany Seagroves, Danielle L. Peacock, Debbie Liao, Luciana P. Schwab, Robin Krueger, Charles R. Handorf, Volker H. Haase, Randall S. Johnson

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Overexpression of hypoxia inducible factor-1 (HIF-1)α, which is common in most solid tumors, correlates with poor prognosis and high metastatic risk in breast cancer patients. Because HIF-1α protein stability is tightly controlled by the tumor suppressor von Hippel-Lindau (VHL), deletion of VHL results in constitutive HIF-1α expression. To determine whether VHL plays a role in normal mammary gland development, and if HIF-1α 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.

Original languageEnglish (US)
Pages (from-to)2269-2282
Number of pages14
JournalAmerican Journal of Pathology
Volume176
Issue number5
DOIs
StatePublished - Jan 1 2010

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Hypoxia-Inducible Factor 1
Carcinogenesis
Breast
Epithelium
Lactation
Human Mammary Glands
Breast Neoplasms
Phenotype
Protein Stability
Microvessels
Lactic Acid
Neoplasms
Epithelial Cells
Cell Proliferation
Hemorrhage
Pregnancy
Growth
Genes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Seagroves, T., Peacock, D. L., Liao, D., Schwab, L. P., Krueger, R., Handorf, C. R., ... Johnson, R. S. (2010). VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis. American Journal of Pathology, 176(5), 2269-2282. https://doi.org/10.2353/ajpath.2010.090310

VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis. / Seagroves, Tiffany; Peacock, Danielle L.; Liao, Debbie; Schwab, Luciana P.; Krueger, Robin; Handorf, Charles R.; Haase, Volker H.; Johnson, Randall S.

In: American Journal of Pathology, Vol. 176, No. 5, 01.01.2010, p. 2269-2282.

Research output: Contribution to journalArticle

Seagroves, T, Peacock, DL, Liao, D, Schwab, LP, Krueger, R, Handorf, CR, Haase, VH & Johnson, RS 2010, 'VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis', American Journal of Pathology, vol. 176, no. 5, pp. 2269-2282. https://doi.org/10.2353/ajpath.2010.090310
Seagroves, Tiffany ; Peacock, Danielle L. ; Liao, Debbie ; Schwab, Luciana P. ; Krueger, Robin ; Handorf, Charles R. ; Haase, Volker H. ; Johnson, Randall S. / VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis. In: American Journal of Pathology. 2010 ; Vol. 176, No. 5. pp. 2269-2282.
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