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Direct Progesterone Receptor and Indirect Androgen Receptor Interactions with the Kallikrein-Related Peptidase 4 Gene Promoter in Breast and Prostate Cancer

Citation

Lai, J and Myers, SA and Lawrence, MG and Odorico, DM and Clements, JA, 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. 129-41. ISSN 1541-7786 (2009) [Refereed Article]

Copyright Statement

Copyright 2009 American Association for Cancer Research

DOI: doi:10.1158/1541-7786.MCR-08-0218

Abstract

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 f2.8 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).

Item Details

Item Type:Refereed Article
Keywords:Nuclear receptor, Prostate
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:Myers, SA (Dr Stephen Myers)
ID Code:100974
Year Published:2009
Web of Science® Times Cited:23
Deposited By:Health Sciences B
Deposited On:2015-06-04
Last Modified:2015-09-18
Downloads:0

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