Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines

Ruth L. Stephen, Mattias C. U. Gustafsson, Morag Jarvis, Roger Tatoud, Barry R. Marshall, Deborah Knight, Ewa Ehrenborg, Adrian L. Harris, C. Roland Wolf, Colin N. A. Palmer

    Research output: Contribution to journalArticle

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    Abstract

    The nuclear receptor peroxisome proliferator-activated receptor d [PPARd/ß (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARd by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARd selective agonists. Activation of PPARd with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARd agonist, GW501516. Conditional expression of PPARd in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARd in the proliferative response to this drug. Activation of PPARd in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor a (VEGFa) and its receptor, FLT-1, thus, suggesting that PPARd may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFa and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARd can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARd antagonists may be of therapeutic value in the treatment of breast and prostate cancer.
    Original languageEnglish
    Pages (from-to)3162-3170
    Number of pages9
    JournalCancer Research
    Volume64
    Issue number9
    DOIs
    Publication statusPublished - May 2004

    Fingerprint

    Peroxisome Proliferator-Activated Receptors
    Prostatic Neoplasms
    Breast Neoplasms
    Cell Line
    Vascular Endothelial Growth Factor A
    Doxycycline
    Human Umbilical Vein Endothelial Cells
    Gonadal Steroid Hormones
    Cytoplasmic and Nuclear Receptors
    Growth
    Prostate
    Molecular Biology
    Colon
    Carcinogenesis
    Breast
    Endothelial Cells
    Cell Culture Techniques
    Steroids
    Cell Proliferation
    Pharmacology

    Cite this

    Stephen, Ruth L. ; Gustafsson, Mattias C. U. ; Jarvis, Morag ; Tatoud, Roger ; Marshall, Barry R. ; Knight, Deborah ; Ehrenborg, Ewa ; Harris, Adrian L. ; Wolf, C. Roland ; Palmer, Colin N. A. / Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines. In: Cancer Research. 2004 ; Vol. 64, No. 9. pp. 3162-3170.
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    title = "Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines",
    abstract = "The nuclear receptor peroxisome proliferator-activated receptor d [PPARd/{\ss} (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARd by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARd selective agonists. Activation of PPARd with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARd agonist, GW501516. Conditional expression of PPARd in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARd in the proliferative response to this drug. Activation of PPARd in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor a (VEGFa) and its receptor, FLT-1, thus, suggesting that PPARd may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFa and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARd can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARd antagonists may be of therapeutic value in the treatment of breast and prostate cancer.",
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    Activation of peroxisome proliferator-activated receptor δ stimulates the proliferation of human breast and prostate cancer cell lines. / Stephen, Ruth L.; Gustafsson, Mattias C. U.; Jarvis, Morag; Tatoud, Roger; Marshall, Barry R.; Knight, Deborah; Ehrenborg, Ewa; Harris, Adrian L.; Wolf, C. Roland; Palmer, Colin N. A.

    In: Cancer Research, Vol. 64, No. 9, 05.2004, p. 3162-3170.

    Research output: Contribution to journalArticle

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    AU - Stephen, Ruth L.

    AU - Gustafsson, Mattias C. U.

    AU - Jarvis, Morag

    AU - Tatoud, Roger

    AU - Marshall, Barry R.

    AU - Knight, Deborah

    AU - Ehrenborg, Ewa

    AU - Harris, Adrian L.

    AU - Wolf, C. Roland

    AU - Palmer, Colin N. A.

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    AB - The nuclear receptor peroxisome proliferator-activated receptor d [PPARd/ß (NR1C2)] has been implicated in colorectal carcinogenesis by various molecular genetic observations. These observations have recently been supported by studies of activation of PPARd by pharmacological agents. Here we present the first report of the stimulation of breast and prostate cancer cell growth using PPARd selective agonists. Activation of PPARd with compound F stimulated proliferation in breast (T47D, MCF7) and prostate (LNCaP, PNT1A) cell lines, which are responsive to sex hormones. Conversely, we have found that several steroid-independent cell lines, including colon lines, were unresponsive to compound F. These findings were confirmed with an additional high-affinity PPARd agonist, GW501516. Conditional expression of PPARd in MCF7 Tet-On cells resulted in a doxycycline-enhanced response to GW501516, thus providing direct genetic evidence for the role of PPARd in the proliferative response to this drug. Activation of PPARd in T47D cells resulted in increased expression of the proliferation marker Cdk2 and also vascular endothelial growth factor a (VEGFa) and its receptor, FLT-1, thus, suggesting that PPARd may initiate an autocrine loop for cellular proliferation and possibly angiogenesis. Consistent with this hypothesis, we demonstrated a pro-proliferative effect of GW501516 on human umbilical vein endothelial cell cultures and found that GW501516 also regulated the expression of VEGFa and FLT-1 in these cells. Our observations provide the first evidence that activation of PPARd can result in increased growth in breast and prostate cancer cell lines and primary endothelial cells and supports the possibility that PPARd antagonists may be of therapeutic value in the treatment of breast and prostate cancer.

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    SN - 0008-5472

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