HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice

Louise R. Howe, Sung Hee Chang, Kelly C. Tolle, Rachelle Dillon, Lawrence J.T. Young, Robert Cardiff, Robert A. Newman, Peiying Yang, Howard T. Thaler, William J. Muller, Clifford Hudis, Anthony M.C. Brown, Timothy Hla, Kotha Subbaramaiah, Andrew J. Dannenberg

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Abstract

The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in ∼40% of human breast cancers and at higher frequencies in preinvasive ductal carcinoma in situ (DCIS). Cox-2 expression is particularly associated with overexpression of human epidermal growth factor receptor 2 (HER2/neu). To definitively interrogate the role of Cox-2 in mammary neoplasia, we have used a genetic approach, crossing Cox-2-deficient mice with a HER2/neu transgenic strain, MMTV/NDL. At 20 weeks of age, mammary glands from virgin MMTV/NDL females contained multiple focal tumors, or mammary intraepithelial neoplasiae, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E2 (PGE2) levels were significantly decreased in Cox-2 heterozygous and knockout animals relative to Cox-2 wild-type controls. Notably, the proportion of larger tumors was decreased in Cox-2-deficient mice. HER2/neu-induced mammary hyperplasia was also substantially reduced in Cox-2 null mice. Additionally, mammary glands from Cox-2 knockout mice exhibited a striking reduction in vascularization, and expression of proangiogenic genes was correspondingly reduced. Decreased vascularization was observed both in dysplastic and normal-appearing regions of Cox-2-null mammary glands. Our data provide the first genetic evidence that Cox-2 contributes to HER2/neu-induced mammary tumorigenesis. This finding may help to explain the reduced risk of breast cancer associated with regular use of nonsteroidal anti-inflammatory drugs.

Original languageEnglish (US)
Pages (from-to)10113-10119
Number of pages7
JournalCancer Research
Volume65
Issue number21
DOIs
StatePublished - Nov 1 2005

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Cyclooxygenase 2
Knockout Mice
Carcinogenesis
Breast
Human Mammary Glands
Carcinoma, Intraductal, Noninfiltrating
Prostaglandin-Endoperoxide Synthases
Breast Neoplasms
Neoplasms
Carcinoma in Situ
Dinoprostone
Hyperplasia
Anti-Inflammatory Agents
Gene Expression
Pharmaceutical Preparations
Mouse Ptgs2 protein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Howe, L. R., Chang, S. H., Tolle, K. C., Dillon, R., Young, L. J. T., Cardiff, R., ... Dannenberg, A. J. (2005). HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Research, 65(21), 10113-10119. https://doi.org/10.1158/0008-5472.CAN-05-1524

HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. / Howe, Louise R.; Chang, Sung Hee; Tolle, Kelly C.; Dillon, Rachelle; Young, Lawrence J.T.; Cardiff, Robert; Newman, Robert A.; Yang, Peiying; Thaler, Howard T.; Muller, William J.; Hudis, Clifford; Brown, Anthony M.C.; Hla, Timothy; Subbaramaiah, Kotha; Dannenberg, Andrew J.

In: Cancer Research, Vol. 65, No. 21, 01.11.2005, p. 10113-10119.

Research output: Contribution to journalArticle

Howe, LR, Chang, SH, Tolle, KC, Dillon, R, Young, LJT, Cardiff, R, Newman, RA, Yang, P, Thaler, HT, Muller, WJ, Hudis, C, Brown, AMC, Hla, T, Subbaramaiah, K & Dannenberg, AJ 2005, 'HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice', Cancer Research, vol. 65, no. 21, pp. 10113-10119. https://doi.org/10.1158/0008-5472.CAN-05-1524
Howe, Louise R. ; Chang, Sung Hee ; Tolle, Kelly C. ; Dillon, Rachelle ; Young, Lawrence J.T. ; Cardiff, Robert ; Newman, Robert A. ; Yang, Peiying ; Thaler, Howard T. ; Muller, William J. ; Hudis, Clifford ; Brown, Anthony M.C. ; Hla, Timothy ; Subbaramaiah, Kotha ; Dannenberg, Andrew J. / HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. In: Cancer Research. 2005 ; Vol. 65, No. 21. pp. 10113-10119.
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abstract = "The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in ∼40{\%} of human breast cancers and at higher frequencies in preinvasive ductal carcinoma in situ (DCIS). Cox-2 expression is particularly associated with overexpression of human epidermal growth factor receptor 2 (HER2/neu). To definitively interrogate the role of Cox-2 in mammary neoplasia, we have used a genetic approach, crossing Cox-2-deficient mice with a HER2/neu transgenic strain, MMTV/NDL. At 20 weeks of age, mammary glands from virgin MMTV/NDL females contained multiple focal tumors, or mammary intraepithelial neoplasiae, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E2 (PGE2) levels were significantly decreased in Cox-2 heterozygous and knockout animals relative to Cox-2 wild-type controls. Notably, the proportion of larger tumors was decreased in Cox-2-deficient mice. HER2/neu-induced mammary hyperplasia was also substantially reduced in Cox-2 null mice. Additionally, mammary glands from Cox-2 knockout mice exhibited a striking reduction in vascularization, and expression of proangiogenic genes was correspondingly reduced. Decreased vascularization was observed both in dysplastic and normal-appearing regions of Cox-2-null mammary glands. Our data provide the first genetic evidence that Cox-2 contributes to HER2/neu-induced mammary tumorigenesis. This finding may help to explain the reduced risk of breast cancer associated with regular use of nonsteroidal anti-inflammatory drugs.",
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AU - Young, Lawrence J.T.

AU - Cardiff, Robert

AU - Newman, Robert A.

AU - Yang, Peiying

AU - Thaler, Howard T.

AU - Muller, William J.

AU - Hudis, Clifford

AU - Brown, Anthony M.C.

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AU - Subbaramaiah, Kotha

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