Genetic mapping studies for familial prostate cancer have identified numerous chromosomal regions linked to prostate cancer susceptibility. On chromosome one a genetic association has been demonstrated between clinically significant prostate cancer and the brain tumor glioblastoma multiforme at 1p36 (CArcinoma Prostate Brain, CAPB), suggesting the presence of a common oncogene for these tumors [
1‐
3]. Using bioinformatics based analysis of text mining and gene expression data we have identified candidate genes within the CAPB locus. One of these genes is HSPG2 (Perlecan). Perlecan is a heparan sulfate proteoglycan that is secreted into the extracellular matrix and can bind growth factors [
4]. Thus Perlecan can act as a reservoir or modulator of growth factor function. One growth factor associated with Perlecan is Hedgehog [
5]. Sonic Hedgehog signaling has recently been shown to be critical for cancer growth and metastasis in multiple tumor types [
6]. In a large proportion of prostate cancers high levels of
Sonic Hedgehog expression is observed along with expression of multiple members of the Hedgehog signaling pathway such as its receptor
Patched1, downstream transcription factor
Gli1, and intracellular modulator
Hedgehog Interacting Protein [
7,
8]. Activation of the Hedgehog pathway has been detected in metastatic prostate tumors [
8,
9], and higher levels of pathway activity are associated with the metastatic phenotype [
9]. Blocking the Sonic Hedgehog pathway with cyclopamine inhibits proliferation of prostate cancer cell lines [
7‐
9] and primary prostate tumor cell cultures [
7]. Treatment of mice with cyclopamine results in the inhibition of tumor xenograft growth in multiple tumor types, including prostate tumors [
7,
10]. Our bioinformatics analyses [
6,
7] suggested that genes encoding two components of the Sonic Hedgehog pathway,
Suppressor of Fused (
Su(fu)) and
Smoothened, the target of cyclopamine, lie in chromosomal regions implicated in familial prostate cancer [
11,
12]. Su(fu) is a negative regulator of pathway activity, thus loss of Su(fu) function would increase Sonic Hedgehog activity. Molecular analyses of prostate tumors revealed that Su(fu) protein is absent in most highly aggressive tumors and somatic truncation mutations in the
Su(fu) gene have been identified [
8] consistent with the hypothesis that
Su(fu) would act as a prostate tumor suppressor gene by inhibiting Sonic Hedgehog signaling. These studies demonstrate the critical nature of Sonic Hedgehog signaling in tumorigenesis and metastasis. Thus identification of additional mechanisms for the regulation of Sonic Hedgehog signaling in cancer takes on added importance. Here we demonstrate that expression of the candidate CAPB gene
HSPG2 (
Perlecan) is present in prostate cancers, up-regulated in aggressive prostate cancers and under poor cell growth conditions, and regulates prostate cancer cell proliferation. In addition, we demonstrate that Perlecan's effects on cell growth are independent of androgen signaling and occur through the binding of Sonic Hedgehog, resulting in modulation of the Sonic Hedgehog-Patched-Gli signaling pathway. This data, along with data linking Perlecan to metastatic tumor environments such a bone matrix [
13], presents a general model in which
Perlecan expression by tumor cells under poor growth conditions enhances their ability to utilize growth factors until their spread to suitable metastatic tumor microenvironments for accelerated growth.