Direct progesterone receptor and indirect androgen receptor interactions with the Kallikrein-Related peptidase 4 gene promoter in breast and prostate cancer

Lai, John, Myers, Stephen A., Lawrence, Mitchell, Odorico, Dimitri M., & Clements, Judith A. (2009) Direct progesterone receptor and indirect androgen receptor interactions with the Kallikrein-Related peptidase 4 gene promoter in breast and prostate cancer. Molecular Cancer Research, 7(1), pp. 129-141.

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Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at –2419 bp and –1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor 2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (–2496 to –2283), which harbors K4.pPRE. This is the first study to show that progesterone-regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at –2419 bp. (Mol Cancer Res 2009;7(1):129–41)

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ID Code: 19582
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Prostate Cancer, Breast Cancer, Protease, Progesterone, Androgen
DOI: 10.1158/1541-7786.MCR-08-0218
ISSN: 1541-7786
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Past > Schools > School of Life Sciences
Copyright Owner: Copyright 2009 American Association for Cancer Research
Deposited On: 15 Apr 2009 22:53
Last Modified: 29 Feb 2012 14:12

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