4.7 Article

Antiangiogenic Tetrathiomolybdate Protects against Her2/neu-Induced Breast Carcinoma by Hypoplastic Remodeling of the Mammary Gland

Journal

CLINICAL CANCER RESEARCH
Volume 15, Issue 23, Pages 7441-7446

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-1361

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Funding

  1. NIH [R01CA77612, P30CA46592, M01-131300042, T32CA09676]
  2. Head and Neck Specialized Program of Research Excellence [P50CA97248]
  3. Susan G. Komen Breast Cancer Foundation
  4. Department of Defense Breast Cancer Research Program Postdoctoral Fellowship
  5. Burroughs Wellcome Fund
  6. Breast Cancer Research Foundation
  7. Department of Defense [DAMD17-02-10490]
  8. Tempting Tables Organization, Muskegon, MI
  9. Attenuon, LLC

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Purpose: The objective of the present study was to delineate the efficacy of tetrathiomolybdate (TM), a novel antiangiogenic anticancer agent, as a chemopreventative agent. Experimental Design: Nulliparous Her2/neu transgenic mice were treated with water or TM for 180 days and observed for tumor development during treatment and for 180 days after treatment. Mammary gland composition and architecture were also observed following TM treatment of Her2/neu transgenic and normal FVB mice. Results: At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice had palpable mammary tumors with a median time to tumor development of 234 days (95% confidence interval, 202-279 days) for control and >460 days for TM-treated mice (P < 0.0005, n = 15). The mammary glands from TM-treated Her2/neu and FVB mice showed a blunted epithelial ductal branching system due to a significant decrease in the number of secondary branches and total number of differentiated mammary epithelial cells. Microvessel density in Her2/neu and FVB mammary glands was lowered by 65.6 +/- 6.2% and 50.9 +/- 4.5% (P < 0.005), respectively, following TM therapy, consistent with the antiangiogenic effect of TM. Lastly, TM treatment resulted in a 2-fold increase in the absolute number of aldehyde dehydrogenase-positive mammary stem cells in Her2/neu and FVB mammary glands. Conclusion: Taken together, these results strongly support that TM is a potent chemopreventative agent as a consequence of hypoplastic remodeling of the mammary gland through modulation of the mammary stem cell compartment. (Clin Cancer Res 2009;15(23):7441-6)

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