Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation

Authors

  • Sanjeev K. Baniwal,

    Corresponding author
    1. Departments of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California
    2. Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    • University of Southern California Keck School of Medicine, Institute for Genetic Medicine, 2250 Alcazar Street, CSC 240, Los Angeles, CA 90033.
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  • Gillian H. Little,

    1. Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    2. Departments of Biochemistry & Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California
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  • Nyam-Osor Chimge,

    1. Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    2. Departments of Biochemistry & Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California
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  • Baruch Frenkel

    Corresponding author
    1. Departments of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, California
    2. Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
    3. Departments of Biochemistry & Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles, California
    • University of Southern California Keck School of Medicine, Institute for Genetic Medicine, 2250 Alcazar Street, CSC 240, Los Angeles, CA 90033.
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    • BF Holds the J. Harold and Edna L. LaBriola Chair in Genetic Orthopedic Research at USC.


  • Conflict of interest: None

Abstract

Prolactin-Induced Protein (PIP) is a small polypeptide expressed by breast and prostate cancer (BCa, PCa) cells. However, both the regulation of PIP expression and its function in cancer cells are poorly understood. Using BCa and PCa cells, we found that Runx2, a pro-metastatic transcription factor, functionally interacts with the Androgen Receptor (AR) to regulate PIP expression. Runx2 expression in C4-2B PCa cells synergized with AR to promote PIP expression, whereas its knockdown in T47D BCa cells abrogated basal as well as hormone stimulated PIP expression. Chromatin immunoprecipitation (ChIP) assays showed that Runx2 and AR co-occupied an enhancer element located ∼11 kb upstream of the PIP open reading frame, and that Runx2 facilitated AR recruitment to the enhancer. PIP knockdown in T47D cells compromised DHT-stimulated expression of multiple AR target genes including PSA, FKBP5, FASN, and SGK1. The inhibition of AR activity due to loss of PIP was attributable at least in part to abrogation of its nuclear translocation. PIP knockdown also suppressed T47D cell proliferation driven by either serum growth factors or dihydrotestosterone (DHT). Our data suggest that Runx2 controls a positive feedback loop between androgen signaling and PIP, and pharmacological inhibition of PIP may be useful to treat PIP positive tumors. J. Cell. Physiol. 227: 2276–2282, 2012. © 2011 Wiley Periodicals, Inc.

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