COX‐2 expression in DCIS: correlation with VEGF, HER‐2/<i>neu</i>, prognostic molecular markers and clinicopathological features

Perrone, Giuseppe; Santini, D.; Vincenzi, Bruno; Zagami, Mariagiovanna; Cesa, Annalisa La; Bianchi, Attilio Antonio Montano; Altomare, Vittorio; Primavera, A. T.; Battista, C.; Vetrani, A; Tonini, Giuseppe; Rabitti, Carla

doi:10.1111/j.1365-2559.2005.02132.x

Cited by 52 publications

(61 citation statements)

References 33 publications

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“…COX-2 has been shown to be expressed in both ductal carcinoma in situ and invasive ductal carcinoma, but not in normal breast tissue in several research articles [16][17][18]. We also saw COX-2 expression in invasive ductal carcinoma, lobular carcinoma and ductal carcinoma in situ but not in fibroadenoma and benign breast disease (Figs.…”

Section: Discussionsupporting

confidence: 54%

Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer

Jana

Sarkar

Ganguly

et al. 2014

Indian J Surg Oncol

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COX-2 regulates tumour growth, invasion and metastasis in breast cancer. This study investigated the association between COX-2 expression in human breast cancer versus the expression of ER, PR, HER-2/neu, as well as its association with other established prognostic indicators like age, menopausal status, tumour size, lymph nodal status, stage, grade, NPI and histological subtype, and aims to validate the role of overexpression of COX-2 as a prognostic marker in patients with breast cancer in Indian subcontinent. In this hospital based study of 123 breast cancer patients (Group-A) and 76 female patients with benign breast disease (Group-B) attending a Comprehensive Breast Clinic at a reputed institute in Eastern India, COX-2 protein expression was measured from breast tissue using the Western Blot Technique. COX-2 mRNA expression was measured by RT-PCR Technique. ER, PR and HER-2/neu status was measured by immunohistochemistry methods. COX-2 was not expressed in the control group. The proportion of COX-2 positive tumours was significantly higher in patients of age . Risk of COX-2 positivity was found to be 2.74 times more for postmenopausal status, 6.90 times more for large size tumours (≥ 2.5), 34.37 times more for node positive tumours, 9.26 times more with ER negative patients and 5.88 times more for PR negative patients. COX-2 expression is associated with established indicators of poor prognosis such as postmenopausal status, age >50 year, advanced stage of disease, large tumour size, higher grade, lymph node metastasis, NPI≥5.4, ER negativity, PR negativity and HER-2/neu positivity. Thus, COX-2 expression implies aggressive tumour biology, and may play an important role as a prognostic marker.

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Section: Discussionsupporting

confidence: 54%

Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer

Jana

Sarkar

Ganguly

et al. 2014

Indian J Surg Oncol

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“…The study revealed the presence of COX-2 protein in 13 of 13 invasive human breast tumors, but not in samples of normal breast tissue. There was a statistically significant linear association between COX-2 and high (> 50%) tumor cell density (P < 0.01) with COX-2 protein localized to tumor cells.Subsequently, molecular biologists from multiple independent laboratories have consistently observed COX-2 over-expression in all stages of breast cancer [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] . Figure 1 shows the mean frequency of specimens over-expressing COX-2 in the progression of mammary carcinogenesis.…”

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confidence: 99%

“…Significantly elevated frequencies of specimens with high COX-2 expression were also observed in premalignant lesions such as atypical hyperplasia (44%) and ductal carcinoma in situ (65%). Furthermore, several of the studies suggest that COX-2 expression is correlated with the metastatic spread of breast cancer and has strong potential as a prognostic indicator of disease severity and progression [30,31,35,[37][38][39] . By comparison, all studies have found negligible or very weak focal COX-2 expression in normal tissues.…”

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confidence: 99%

“…Molecular studies from multiple laboratories reveal that adenocarcinoma of the breast is characterized by aberrant over-expression of COX-2 by breast cancer epithelial cells [24,[33][34][35][36][37][38] . As shown by Karmali et al [116] Rose et al [117] , and others [33][34][35][36][37][38] , arachidonic acid production, COX-2 expression, and prostaglandin biosynthesis are increased in vivo by dietary n-6 polyunsaturated fatty acids (n-6-PUFAs) such as unconjugated linoleic acid, and decreased by n-3-PUFAs such as linolenic acid. High dietary intake of n-6-PUFAs may therefore be an important factor in the induction of constitutive COX-2 expression.…”

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confidence: 99%

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Cyclooxygenase-2 and the inflammogenesis of breast cancer

Harris

Casto

Harris

2014

WJCO

154

125

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Cohesive scientific evidence from molecular, animal, and human investigations supports the hypothesis that constitutive overexpression of cyclooxygenase-2 (COX-2) is a ubiquitous driver of mammary carcinogenesis, and reciprocally, that COX-2 blockade has strong potential for breast cancer prevention and therapy. Key findings include the following: (1) COX-2 is constitutively expressed throughout breast cancer development and expression intensifies with stage at detection, cancer progression and metastasis; (2) essential features of mammary carcinogenesis (mutagenesis, mitogenesis, angiogenesis, reduced apoptosis, metastasis and immunosuppression) are linked to COX-2-driven prostaglandin E2 (PGE-2) biosynthesis; (3) upregulation of COX-2 and PGE-2 expression induces transcription of CYP-19 and aromatase-catalyzed estrogen biosynthesis which stimulates unbridled mitogenesis; (4) extrahepatic CYP-1B1 in mammary adipose tissue converts paracrine estrogen to carcinogenic quinones with mutagenic impact; and (5) agents that inhibit COX-2 reduce the risk of breast cancer in women without disease and reduce recurrence risk and mortality in women with breast cancer. Recent sharp increases in global breast cancer incidence and mortality are likely driven by chronic inflammation of mammary adipose and upregulation of COX-2 associated with the obesity pandemic. The totality of evidence clearly supports the supposition that mammary carcinogenesis often evolves as a progressive series of highly specific cellular and molecular changes in response to induction of constitutive overexpression of COX-2 and the prostaglandin cascade in the "inflammogenesis of breast cancer". Key words: Breast Cancer; Cyclooxygenase-2; Nonsteroidal anti-inflammatory drugs; Inflammogenesis; Estrogen; Aromatase Core tip: Mammary carcinogenesis often evolves as a series of highly specific cellular and molecular changes in response to induction of constitutive over-expression of cyclooxygenase-2 (COX-2) and the prostaglandin cascade; reciprocally, agents that block COX-2 have significant value in the chemoprevention and therapy of breast cancer.Harris RE, Casto BC, Harris ZM. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol 2014; 5(4): 677-692 Available from: URL: http://www.wjgnet.com/2218-4333/full/v5/ i4/677.htm DOI: http://dx.doi.org/10.5306/wjco.v5.i4.677 INTRODUCTIONMore than a century ago, Virchow et al [1,2] chronic inflammation leads to cancer development by increasing cellular proliferation [3] . Various models of carcinogenesis have been proposed involving inflammatory stimuli and mediators of wound healing [4][5][6] . The recent discovery of the inducible cyclooxygenase-2 (COX-2) gene has rekindled interest in the causal link between inflammation and cancer, and various models of carcinogenesis have been proposed involving inflammatory stimuli and COX-2 expression [7][8][9][10] . The current review synthesizes and interprets the accumulating body of evidence supporting COX-2 driven inflammogenesis as a ge...

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“…23 Although VEGF-C production and lymphangiogenesis was a direct consequence of COX-2 expression in human breast cancer, 17 we found that HER-2, often co-expressed with COX-2 in human breast cancer, had no direct role in VEGF-C upregulation or lymphangiogenesis, and that its role, if any, was COX-2 dependent. 21 The facts that COX-2 is overexpressed in about half of breast cancer specimens 7 inclusive of DCIS 24 and invasive carcinomas, 21 and has multiple roles in breast cancer progression and metastasis, make this molecule a reasonable therapeutic target. Recent safety concerns related to the cardiovascular side effects of high dose COX-2 inhibitors 25,26 have led to the search for alternative targets downstream of COX-2, which would spare the vaso-protective prostacyclins.…”

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confidence: 99%

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

Xin

Majumder

Girish

et al. 2012

Laboratory Investigation

115

160

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We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.

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COX‐2 expression in DCIS: correlation with VEGF, HER‐2/neu, prognostic molecular markers and clinicopathological features

Abstract: Our results suggest that COX-2 is highly expressed in DCIS and takes part in the molecular pathway implicated in progression of breast cancer and may provide a rationale for targeting COX-2 in preinvasive breast cancer therapy.

Cited by 52 publications

References 33 publications

Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer

Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer

Cyclooxygenase-2 and the inflammogenesis of breast cancer

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

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