Effect of hormonal status on the expression of the cyclooxygenase 1 and 2 genes and prostaglandin synthesis in rat mammary glands

Badawi, Alaa; Archer, Michael C.

doi:10.1016/s0090-6980(98)00049-5

Cited by 27 publications

(8 citation statements)

References 38 publications

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“…Thus, high PGE 2 levels appear to be associated with terminal differentiation, rather than proliferation of mammary epithelium during normal gland development. These findings are also consistent with those previously reported for the rodent mammary gland (21), in which PGE 2 levels were found to be lower in the resting virgin gland and highest in lactating mammary glands. PGE 2 metabolic enzymes are reported to have tissuespecific expression patterns and are putatively regulated by specific stimuli and cellular stresses.…”

Section: Discussionsupporting

confidence: 93%

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Chandrasekharan

Foley

Jania

et al. 2005

Journal of Lipid Research

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The mammary gland, like most tissues, produces measurable amounts of prostaglandin E 2 (PGE 2 ), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E 2 synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E 2 synthase (cPGES). High PGE 2 levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE 2 metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE 2 biosynthesis are poorly understood. We demonstrate that expression of COX-1, generally considered constitutive, increases dramatically with lactogenic differentiation of the murine mammary gland. Concordantly, total PGE 2 levels increase throughout mammary development, with highest levels measured in lactating tissue and breast milk. In contrast, COX-2 expression is extremely low, with only a modest increase detected during mammary involution. Expression of the G s -coupled PGE 2 receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE 2 production is dependent on COX-1, as PGE 2 levels are nearly undetectable in COX-1 -deficient mammary glands. Interestingly, PGE 2 levels are similarly reduced in lactating glands of mPGES1 -deficient mice, indicating that PGE 2 biosynthesis results from the coordinated activity of COX-1 and mPGES1. We thus provide evidence for the first time of functional coupling between COX-1 and mPGES1 in the murine mammary gland in vivo.

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Section: Discussionsupporting

confidence: 93%

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Chandrasekharan

Foley

Jania

et al. 2005

Journal of Lipid Research

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“…Total RNA was extracted by TRIzol reagent (Invitrogen, Carlsbad, CA) from mammary epithelial cells that were isolated from the whole mammary tissue as described previously (42). RNA was subjected to reverse transcription-PCR reaction using Titanium One-Step Reverse Transcription-PCR (Clontech, Palo Alto, CA) protocol (10).…”

Section: Analysis Of Mrna and Protein Expressionmentioning

confidence: 99%

“…PCR products were separated in 1.5-2% agarose gels and visualized by ethidium bromide staining. Appropriate negative controls were carried out as described previously (41,42) to rule out contamination of RNA with genomic DNA and to ensure that no cDNA synthesis would occur before reverse transcriptase inactivation. Digitized images of the stained cDNA products were captured as 8-bit digital TIFF files using a DC290 Digital Camera (Eastman Kodak Co., Rochester, NY).…”

Section: Analysis Of Mrna and Protein Expressionmentioning

confidence: 99%

Inhibition of Rat Mammary Gland Carcinogenesis by Simultaneous Targeting of Cyclooxygenase-2 and Peroxisome Proliferator-activated Receptor γ

et al. 2004

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We examined the effect of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, and N-(9-fluorenyl-methyloxycarbonyl)-L-leucine (F-L-Leu), a peroxisome proliferator-activated receptor ␥ (PPAR␥) agonist, separately and combined, on the development of methylnitrosourea (MNU)-induced rat mammary gland carcinogenesis. Celecoxib and F-L-Leu significantly reduced tumor incidence and multiplicity (P < 0.05). Combining both agents exerted higher (synergistic) cancer inhibition than separate treatments (P < 0.05). The effects of the test drugs on COX-2 and PPAR␥ expression and on the synthesis of prostaglandin E 2 (PGE 2 ) and 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ) were examined in rat mammary normal (MNUuntreated), uninvolved, and tumor (MNU-treated) tissues. Celecoxib and F-L-Leu, separately, inhibited COX-2 and up-regulated PPAR␥ expression. These effects were paralleled by inhibition of PGE 2 synthesis and up-regulation of 15d-PGJ 2 . Combined treatment resulted in higher alterations in COX-2 and PPAR␥ transcripts and PG synthesis compared with separate administrations. The effect of the test agents on Bcl 2 , BAX, and protein kinase C␣ expression levels were examined in the rat mammary gland and the pro-(BAX:Bcl 2 ) and anti-[PKC␣*(Bcl 2 /BAX)] apoptotic ratios were evaluated. Each drug increased the proapoptotic ratio by 2-to 7-fold and reduced the antiapoptotic ratio by 2-to >8-fold in all tissues. Combined treatment, however, resulted in >9-to 14-fold up-regulation in the proapoptotic processes and 15-to >30-fold down-regulation in the antiapoptotic ones. Analyses were also carried out on the drug-induced modulation of cell cycle regulators and proliferation markers (cyclindependent kinase 1 and proliferating cell nuclear antigen). F-L-Leu and celecoxib each reduced the cyclin-dependent kinase 1 and proliferating cell nuclear antigen expression in the tumor. Higher down-regulation was attained in all tissues by combined treatment where cyclin-dependent kinase 1 and proliferating cell nuclear antigen almost retained the expression levels observed in the normal glands. In conclusion, simultaneous targeting of COX-2 and PPAR␥ may inhibit mammary cancer development more effectively than targeting each molecule alone. COX-2 inhibitors and PPAR␥ agonists coordinately mediate their anticancer effect via both COX-dependent (inhibition of COX-2, activation of PPAR␥, and modulation PG synthesis) and COX-independent (induction of proapoptotic factors and inhibition of cell proliferation) pathways.

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“…Various studies, however, have demonstrated that mammary epithelium and adipose tissues predominantly express PPARs,48, 49 where PPARγ1 is the ubiquitously expressed subtype whereas PPARγ2 is only confined to adipose tissue 7. Similarly, COX‐2 expression and increased levels of PGE 2 occur in both stromal50 and epithelial51 cells of mammary tumor and normal tissues 52. Indeed, levels of COX‐2 and PPARγ1 mRNA and protein were comparable in both mammary stromal and epithelial cells50 (A.F.…”

Section: Discussionmentioning

confidence: 89%

Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E₂ and 15‐deoxy‐Δ^12,14‐prostaglandin J₂ in human breast cancer and metastasis

Badawi

Badr

2002

Intl Journal of Cancer

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Cyclooxygenase-2 (COX-2) expression and peroxisome proliferator-activated receptor-␥ (PPAR␥) inactivation are linked to increased risk of human breast cancer. The purpose of our study was to examine the relationship between COX-2 (with the resulting prostaglandins E 2 , PGE 2 ) and PPAR␥ (and its natural endogenous ligand 15-Deoxy-⌬ 12,14 -prostaglandin J 2 , 15d-PGJ 2 ) at various stages during the development of human breast cancer and its progression to metastasis. Human breast tissue specimens were collected from normal breasts or from individuals with fibrocystic disease and served as controls (n ‫؍‬ 22). Tissues were also collected from uninvolved (n ‫؍‬ 25), tumor (n ‫؍‬ 25) and lymph node metastasis (n ‫؍‬ 15) regions from breast cancer patients. COX-2 and PPAR␥ mRNA expression were increased and downregulated, respectively, in tissues from cancer patients compared to controls. Metastatic tissues tended to have higher alterations compared to non-metastatic tissues (p < 0.05). These altered expressions in COX-2 and PPAR␥ were paralleled by increases in the tissue levels of PGE 2 and decreases in 15d-PGJ 2 . A significant inverse correlation was found between PGE 2 and 15-d-PGJ 2 (r ‫؍‬ ؊0.51, p < 0.05). Significant correlations (p < 0.05) were also obtained between COX-2 and PPAR␥ mRNA (inverse, r ‫؍‬ ؊0.72) and between COX-2 and PGE 2 (direct, r ‫؍‬ 0.68). Increases in COX-2 mRNA expression and levels of PGE 2 and down-regulation of PPAR␥ mRNA expression and 15d-PGJ 2 levels were characterized as predictors of breast cancer risk (p < 0.05). Our results suggest that the altered expression of COX-2 and PPAR␥ and the subsequent modulation in the tissue levels of PGE 2 and 15-d-PGJ 2 may influence the development of human breast cancer and its progression to metastasis. © 2002 Wiley-Liss, Inc. Key words: breast cancer; cyclooxygenases; peroxisome proliferatoractivated receptors; chemopreventionThe high prevalence of breast cancer 1 and the limited options for treatment provide a strong rationale for identifying new, selective molecular targets that can be nutritionally or pharmacologically modulated and, thereby, offer a potential for chemoprevention. Among the regulatory molecules that have been characterized as holding great promise for breast cancer prevention are cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-␥ (PPAR␥). 2 Cyclooxygenase is the rate-limiting enzyme in prostaglandin (PG) synthesis, of which 2 isoforms were identified: the constitutive COX-1 and the inducible COX-2. PGs produced by COX-1 mediate various physiological responses, whereas PGs produced by COX-2, predominantly PGE 2 , induce inflammation and are potent mediators of a number of signal transduction pathways that modulate cell adhesion and growth and are implicated in cancer development. 3 COX-1 and COX-2 are the primary targets of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the activity of these enzymes as a major mode of their anti-tumorigenic action. 4 Recent findings, however, suggest ...

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Effect of hormonal status on the expression of the cyclooxygenase 1 and 2 genes and prostaglandin synthesis in rat mammary glands

Cited by 27 publications

References 38 publications

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Inhibition of Rat Mammary Gland Carcinogenesis by Simultaneous Targeting of Cyclooxygenase-2 and Peroxisome Proliferator-activated Receptor γ

Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E₂ and 15‐deoxy‐Δ^12,14‐prostaglandin J₂ in human breast cancer and metastasis

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Effect of hormonal status on the expression of the cyclooxygenase 1 and 2 genes and prostaglandin synthesis in rat mammary glands

Cited by 27 publications

References 38 publications

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland

Inhibition of Rat Mammary Gland Carcinogenesis by Simultaneous Targeting of Cyclooxygenase-2 and Peroxisome Proliferator-activated Receptor γ

Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E2 and 15‐deoxy‐Δ12,14‐prostaglandin J2 in human breast cancer and metastasis

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Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E₂ and 15‐deoxy‐Δ^12,14‐prostaglandin J₂ in human breast cancer and metastasis