Genetic induction and upregulation of cyclooxygenase (COX) and aromatase (CYP19): an extension of the dietary fat hypothesis of breast cancer

Harris, Randall E.; Robertson, Fredika M.; Abou-Issa, Hussein; Farrar, William B.; Brueggemeier, Robert W.

doi:10.1054/mehy.1998.0009

Cited by 56 publications

(24 citation statements)

References 11 publications

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“…The current results help to refine and validate previous models that have attempted to explain the stimulatory effects of PGE 2 on estrogen biosynthesis (43,44). Overexpression of COX-2 in breast cancer cells leads to increased PGE 2 synthesis (Fig.…”

Section: Discussionsupporting

confidence: 76%

HER-2/neu Status Is a Determinant of Mammary Aromatase Activity In vivo: Evidence for a Cyclooxygenase-2-Dependent Mechanism

Subbaramaiah

Howe

Port³

et al. 2006

Cancer Research

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Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the synthesis of estrogens from androgens. Given the significance of estrogen synthesis in hormone-dependent breast carcinogenesis, it is important to elucidate the mechanisms that regulate CYP19 expression. The main objective of this study was to define the interrelationship between HER-2/neu, cyclooxygenase-2 (COX-2), and aromatase in mammary tissue. Mammary aromatase activity and prostaglandin E 2 (PGE 2 ) levels were increased in mice with mammary-targeted expression of a COX-2 transgene. In vitro, overexpressing COX-2 caused both increased PGE 2 production and aromatase activity, effects that were suppressed by celecoxib, a selective COX-2 inhibitor. Previously, we found that overexpression of HER-2/neu was associated with increased levels of COX-2 in human breast cancers. Here, we show that overexpression of HER-2/neu is also associated with increased aromatase activity. These results suggested the possibility that COX-2 was the functional intermediate linking HER-2/neu and aromatase. Consistent with this idea, COX-2 deficiency led to a gene dose-dependent reduction in mammary aromatase activity in a HER-2/neu transgenic mouse model. Complementary in vitro studies showed that HER-2/ neu-mediated induction of PGE 2 synthesis and aromatase activity were suppressed by inhibiting COX-2. Collectively, our data indicate that COX-2 is the functional intermediate linking HER-2/neu and aromatase and suggest that inhibitors of PGE 2 synthesis will suppress estrogen biosynthesis in breast tissue. (Cancer Res 2006; 66(10): 5504-11)

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Section: Discussionsupporting

confidence: 76%

HER-2/neu Status Is a Determinant of Mammary Aromatase Activity In vivo: Evidence for a Cyclooxygenase-2-Dependent Mechanism

Subbaramaiah

Howe

Port³

et al. 2006

Cancer Research

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“…This mechanism is compatible with the high rates of cancers of the breast, colon and prostate (neoplasms that characteristically over-express COX-2) in populations where n-6-PUFAs, particularly unconjugated linoleic acid, are abundant in the diet. The COX-2 enzyme efficiently catalyzes the conversion of essential dietary fats (principally arachidonic acid and unconjugated linoleic acid) into prostaglandins [100,113,118] . Obesity has reached epidemic proportions in most industrialized nations in association with increased rates of a variety of chronic conditions such as type 2 diabetes, coronary heart disease and certain malignant neoplasms including breast cancer.…”

Section: Induction Of Cox-2mentioning

confidence: 99%

“…Furthermore, COX-2 driven PGE-2 biosynthesis induces transcription of CYP-19 and aromatase-catalyzed production of estrogen in a paracrine mechanism. Local estrogen biosynthesis in the breast parenchyma has been hypothesized to be a key feature of breast cancer development, particularly in postmenopausal women [112,113] . …”

mentioning

confidence: 99%

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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“…It has been demonstrated that PGE2 stimulates aromatase transcription leading to increased concentrations of oestrogens (Harris et al, 1999). Overexpression of COX-2 in breast cancer may lead to increased PGE2 synthesis and this in turn to progression of oestrogen-dependent disease.…”

Section: Cox-2 As a Potential Target For Prevention And Treatment Of mentioning

confidence: 99%

COX inhibitors and breast cancer

2006

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There is considerable evidence to suggest that prostaglandins play an important role in the development and growth of cancer. The enzyme cyclo-oxygenase (COX) catalyses the conversion of arachidonic acid to prostaglandins. In recent years, there has been interest in a possible role for COX inhibitors in the prevention and treatment of malignancy. Cyclo-oxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Preclinical evidence favours an antitumour role for COX inhibitors in breast cancer. However, the epidemiological evidence for an association is conflicting. Trials are being conducted to study the use of COX inhibitors alone and in combination with other agents in the chemoprevention of breast cancer, and in the neoadjuvant, adjuvant, and metastatic treatment settings. In evaluating the potential use of these agents particularly in cancer chemoprophylaxis, the safety profile is as important as their efficacy. Concern over the cardiovascular safety of both selective and nonselective COX-inhibitors has recently been highlighted. Breast cancer is the most common malignancy in women in industrialised nations and the second leading cause of female cancer-related mortality. Approximately 40 000 women develop breast cancer in the UK each year. The incidence of breast cancer has increased by two-thirds over the last 15 years. Mortality rates though have fallen by one-third, and this is likely to be due to earlier detection of breast cancer because of screening, and the increased use of adjuvant therapies. In recent times, the prospect of further improvements in mortality rates has grown with hope provided by new chemotherapy agents and monoclonal antibody therapy directed at cell surface molecules. But can we do even better for women with breast cancer using cheap and simple treatments that are in current use?Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of widely available, inexpensive medicines. The analgesic, antiinflammatory, antipyretic and antithrombotic effects of salicylate in willow bark and other plant extracts were recognised in ancient Egypt and Greece. These properties have been extensively exploited in numerous fields of clinical medicine since the 19th century, and in cancer patients primarily for analgesia.

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Genetic induction and upregulation of cyclooxygenase (COX) and aromatase (CYP19): an extension of the dietary fat hypothesis of breast cancer

Cited by 56 publications

References 11 publications

HER-2/neu Status Is a Determinant of Mammary Aromatase Activity In vivo: Evidence for a Cyclooxygenase-2-Dependent Mechanism

HER-2/neu Status Is a Determinant of Mammary Aromatase Activity In vivo: Evidence for a Cyclooxygenase-2-Dependent Mechanism

Cyclooxygenase-2 and the inflammogenesis of breast cancer

COX inhibitors and breast cancer

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