COX-2 involvement in breast cancer metastasis to bone

Singh, Balraj; Berry, Jacob A.; Shoher, Angela; Ayers, Gregory D.; Wei, Caimiao; Lucci, Anthony

doi:10.1038/sj.onc.1210154

Cited by 133 publications

(112 citation statements)

References 32 publications

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“…This effect is closely associated with osteolytic cancer bone metastasis, which involves in bone destruction (2). This knowledge is further supported by reports that administration of cyclooxygenase (COX) inhibitors suppresses the bone metastasis of breast and prostate cancer cells (3,4).…”

Section: Introductionsupporting

confidence: 58%

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Takahashi

Uehara

Bando

et al. 2008

Molecular Cancer Therapeutics

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Prostaglandin E 2 (PGE 2 ) plays a key role in osteolytic bone metastasis as well as roles in inflammation, cell growth, and tumor development. PGE 2 exerts its effects by binding and activating E-prostanoid receptor (EP). In this study, we propose a new approach for blocking EP-mediated cell signaling using a soluble chimeric EP2 fragment. Mammalian expression vectors encoding several human EP2 cDNAs were introduced into 293 cells and the culture medium was tested for their function as a decoy receptor for PGE 2 . PGE 2 binding assays revealed that culture medium containing the second extracellular region of EP2 (FuEP2/Ex2) had binding activity. FuEP2/Ex2 neutralized PGE 2 -induced cyclic AMP production, cyclic AMP -responsive element binding protein phosphorylation, and subsequent induction of cyclooxygenase-2, interleukin (IL)-1B, and IL-6 mRNAs. In human osteoblasts, this culture medium neutralized the induction of receptor activator of nuclear factor-KB ligand mRNA. A stable transfectant expressing FuEP2/Ex2 was established from human prostate cancer PC-3 cells (PC3-FuEP2/Ex2). PC3-FuEP2/Ex2 cells grew at similar rates to vector control cells under normal culture conditions, although PGE 2 -induced growth stimulation was suppressed. Intraosseous injection of PC3-FuEP2/Ex2 cells into the tibia of athymic nude mice revealed that the degrees of tumor growth and osteolysis were decreased compared with control cellinjected mice, with decreased osteoclasts and increased apoptotic cells. Furthermore, the cyclooxygenase-2, IL-1B, and IL-6 mRNA levels were reduced in the tumor lesions. These data suggest that FuEP2/Ex2 is useful for treating osteolytic bone metastasis and cancers that depend on EP signaling for their growth and development.

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Section: Introductionsupporting

confidence: 58%

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Takahashi

Uehara

Bando

et al. 2008

Molecular Cancer Therapeutics

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“…In animal models obtained with mouse (TM40D-MB or 4T1.2) and human (MDA-MB231) cells, COX-2/PGE2 system participates in osteolysis [6,[16][17][18] but the distinct functions contributing to breast-carcinoma metastasis remain largely unknown. HGF/Met couple is important for the cross-talk between metastasis and microenvironment [2], and its activation by hypoxia might be hypothesized based on data from normal and neoplastic cell types [19,20].…”

mentioning

confidence: 99%

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Maroni

Matteucci²,

Luzzati³

et al. 2010

Breast Cancer Res Treat

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The aim of the present paper was to identify nuclear co-localization of COX-2 and HIF-1α in human-bone metastasis of breast cancer, index of transcriptionally-activated cells and functional for gene expression. In particular, we verified whether hypoxia exerted a direct role on metastasis-gene expression or through COX-2 signaling, due to the relevance for clinical implications to individuate molecular targets for diagnosis and therapy. The experiments were performed in vitro with two autoregulatory loops triggered a specific array of transcription factors responsible for COX-2 transactivation. The novelty was that HGF and TGF-β1 biological signals were produced by hypoxic metastatic cells and, therefore, the microenvironment seemed to be modified by metastaticcell engraftment in the bone. In agreement, HIF-1α expression in bone-marrow supportive cells occurred in metastasis-bearing animals. Altogether, the data supported the pre-metastatic-niche theory. Our observations might be useful to design therapies against bone metastasis, by affecting the phenotype changes of metastatic cells occurring at the secondary growth site through COX-2-HIF-1 interaction.Keywords bone microenvironment · bone metastasis · breast cancer · COX-2 · HIF-1 3

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“…Overexpression of cyclooxygenase-2 (COX-2) has been detected in malignant tumors of a variety of tissues, including colon, prostate, lung, breast, and uterine cervix (1)(2)(3)(4)(5). COX-2 is known to play an important role in carcinogenesis by stimulating growth, survival, invasion, metastasis, and angiogenesis of tumor cells (3,4,(6)(7)(8)(9), but its exact role in cancer development has not been well understood.…”

Section: Introductionmentioning

confidence: 99%

“…COX-2 is known to play an important role in carcinogenesis by stimulating growth, survival, invasion, metastasis, and angiogenesis of tumor cells (3,4,(6)(7)(8)(9), but its exact role in cancer development has not been well understood. COX-2 is a 72-kDa protein with 604 amino acids, localized primarily to the endoplasmic reticulum and nuclear membrane.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

Kim

Park

Pyo

2009

Molecular Cancer Research

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Overexpression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment with various drugs (EGF, celecoxib, prostaglandin E 2 , gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2-overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2-overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2-overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy.

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COX-2 involvement in breast cancer metastasis to bone

Cited by 133 publications

References 32 publications

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Soluble EP2 neutralizes prostaglandin E2–induced cell signaling and inhibits osteolytic tumor growth

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

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