Direct Progesterone Receptor and Indirect Androgen Receptor Interactions with the Kallikrein-Related Peptidase 4 Gene Promoter in Breast and Prostate Cancer
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 2009 American Association for Cancer Research
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).