The regulation of intracellular Ca 2؉ plays a key role in the development and growth of cells. Here we report the cloning and functional expression of a highly calciumselective channel localized on the human chromosome 7. The sequence of the new channel is structurally related to the gene product of the CaT1 protein cloned from rat duodenum and is therefore called CaT-like (CaT-L). CaT-L is expressed in locally advanced prostate cancer, metastatic and androgen-insensitive prostatic lesions but is undetectable in healthy prostate tissue and benign prostatic hyperplasia. Additionally, CaT-L is expressed in normal placenta, exocrine pancreas, and salivary glands. New markers with well defined biological function that correlate with aberrant cell growth are needed for the molecular staging of cancer and to predict the clinical outcome. The human CaT-L channel represents a marker for prostate cancer progression and may serve as a target for therapeutic strategies.
Estrogens have been implicated in prostatic cancerogenesis and tumor progression. The mechanisms underlying estrogen signaling in human prostate tissue, however, remain poorly understood. Using immunohistochemical and in situ hybridization (ISH) techniques, the present study demonstrates the classical estrogen receptor (ERalpha) in premalignant lesions and prostatic adenocarcinoma through the various stages of the disease. Conversely, the novel characterized ERbeta subtype was undetectable in human prostate tissue. High-grade prostatic intraepithelial neoplasia revealed ERalpha mRNA and protein expression in 28% and 11% of cases evaluated. Focal ER immunoreactivity was detected in a minority of low- to intermediate-grade adenocarcinoma. High-grade (primary Gleason grade 4 and 5) tumors revealed ER protein expression in 43% (62% respectively) of cases. The most significant ERalpha gene expression on mRNA and protein levels was observed in hormone refractory tumors and metastatic lesions, including lymph node and bone metastases. Results of the current study suggest that estrogens can affect prostatic cancerogenesis and neoplastic progression through an ER-mediated process in human prostate tissue.
To obtain more insight into the proliferative function of basal and secretory cell types in human prostate, we studied the immunoprofile of three well-characterized proliferation-associated antigens (Ki-67, PCNA, MIB 1) in normal and hyperplastic prostate tissue. Distinction between labeled basal and secretory cell types was made by simultaneous demonstration of the proliferation-associated antigens and basal cell-specific cytokeratins in identical sections. In normal and hyperplastic acini, approximately 70% of labeled cells were of the basal cell phenotype. These data clearly suggest that the proliferative compartment of the normal and hyperplastic epithelium is located in the basal cell layer. Compared to normal and hyperplastic conditions, severe proliferative abnormalities were detected in high-grade prostate intraepithelial neoplasias (PIN), as documented by the extension of the proliferative compartment up to the luminal border. Conversely, approximately 70% of proliferating cells detected in atypical hyperplasias that progressed in invasive carcinomas were localized in the remaining basal cell layer. These findings may indicate the proliferative role of basal cells in the epithelial renewal, and the development of hyperplastic and neoplastic disorders in the human prostate.
The secretory epithelium is a major target of ERbeta-mediated estrogen signaling in the human prostate. Its downregulation in HGPIN is consistent with chemopreventive effects that the ERbeta may exert on the prostatic epithelium. The continuous expression of the receptor protein at significant levels in untreated primary and metastatic adenocarcinoma indicates that these tumors can use estrogens through an ERbeta-mediated pathway. The partial loss of the ERbeta in recurrent tumors after androgen-deprivation may reflect the androgen-dependence of ERbeta gene expression in human prostate cancer.
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