HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice

Abstract

The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in f40% 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 neoplasias, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E 2 (PGE 2 ) 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 antiinflammatory drugs. (Cancer Res 2005; 65(21): 10113-9)

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

“…Many studies have demonstrated that transgenic mice that overexpressed COX-2 in mammary glands, skin, and stomach are prone to develop tumours in these organs (Neufang et al, 2001;Muller-Decker et al, 2002;Oshima et al, 2004). In contrast, COX-2 knock-out mice are more resistant to tumorigenesis in various organs (Oshima et al, 1996;Tiano et al, 2002;Howe et al, 2005). A number of clinical studies were performed for colorectal cancer prevention by administration of Nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors including sulindac, aspirin, celecoxib, rofecoxib (Giardiello et al, 1996;Steinbach et al, 2000;Giardiello et al, 2002;Baron et al, 2003;Higuchi et al, 2003;Sandler et al, 2003;Bertagnolli et al, 2006).…”

Regulation of HER-2 oncogene expression by cyclooxygenase-2 and prostaglandin E2

“…Moreover, a recent study demonstrated that COX-2 forced expression in murine mammary gland was sufficient to induce breast cancer in multiparous animals (Liu et al, 2001). Finally, COX-2 overexpression was observed in tumors from MMTV/ neu mice, and its inhibition with celecoxib reduced the incidence of mammary tumors in this model (Howe et al, 2002).…”

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

“…1 Furthermore, COX-2 overexpression is a signature as well as a major determinant of tumor progression and metastasis in a variety of cancers including breast cancer. [1][2][3] In mice, transgenic overexpression of COX-2 induces mammary neoplasia, 4 and its pharmacological inhibition 5 or genetic deletion 6 suppresses HER-2-induced mammary cancer development. COX-2 expression in human breast cancer is correlated with reduced survival, as well as other indicators of poor prognosis, such as increased tumor size, high tumor grade, negative hormone receptor status, HER-2 overexpression, 7 angiogenesis, 8 metastasis to lymph nodes 8,9 and other organs.…”