Distinct Altered Patterns of p27KIP1 Gene Expression in Benign Prostatic Hyperplasia and Prostatic Carcinoma

Cordon‐Cardo, Carlos; Koff, Andrew; Drobnjak, Marija; Capodieci, Paola; Osman, Iman; Millard, S. Sean; Gaudin, Paul B.; Fazzari, Melissa; Zhang, Zuo‐Feng; Massagué, Joan; Scher, Howard I.

doi:10.1093/jnci/90.17.1284

Cited by 267 publications

(162 citation statements)

References 43 publications

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“…Alterations of p27 gene expression have been found in BPH and prostatic carcinoma. 44 In this study, we found that exogenous IGF-1 decreased the p27 protein level in BPH-1 cells. Similarly, intracellular p27 protein levels of BPH-1 cells decreased significantly when co-cultured with c-jun ϩ/ϩ fibroblasts, particularly after 24 hours of co-culture (Figure 6C).…”

Section: Igf-1 and Stromally Expressed C-jun Regulate Cyclin D Levelsmentioning

confidence: 50%

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Febbo

et al. 2007

The American Journal of Pathology

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Stromal-epithelial interactions play a critical role inBenign prostatic hyperplasia (BPH) is the most common age-related proliferative abnormality of the human prostate affecting elderly men throughout the world. Half of all men have BPH identifiable histologically by age 60, and by age 85 the prevalence is ϳ90%. 1 The excessive cell proliferation associated with BPH causes benign prostatic enlargement, bladder outlet obstruction, and lower urinary tract symptoms, which afflict the patients. 2 BPH is a histological diagnosis associated with both epithelial and stromal (fibroblasts and smooth muscle cells of prostate) hyperplasia. 3 Cellular alterations that include changes in proliferation, differentiation, apoptosis, and senescence in the epithelium and stroma are implicated in the pathogenesis of BPH. Medical treatments available to patients with BPH target both prostatic stromal and epithelial cells.Watchful waiting, pharmacological therapy, and surgery are three treatment modalities for BPH patients. Medical therapy is a long-term commitment for the patient. Surveys show that a large number of patients discontinue therapy, often because they perceive lack of efficacy and/or experience side effects. 4,5 We can accordingly improve our treatment of BPH by better targeted medical therapy to decrease the number of invasive therapies for this benign disease. Better alternative and improved therapies can be achieved by studying the normal and abnormal reciprocal cross talk between prostatic stromal and epithelial cells.Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Cunha and colleagues 6 -8 have demonstrated that the stromal embryonic tissue is responsible for instructing the proper development of prostate epithelial cells. Tissue recombinants between embryonic urogenital sinus mesenchyme and adult prostatic tissue have demonstrated that the fetal mesenchyme can drive differentiation and growth of adult prostatic epithelial cells. 9 It has been proposed that BPH may be caused by reactivation of dormant embryonic growth in the adult stroma. 10 The proliferation of the stromal elements can stimulate the ingrowth of epithelial cells to produce a benign hyperplastic growth that is recognized

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Section: Igf-1 and Stromally Expressed C-jun Regulate Cyclin D Levelsmentioning

confidence: 50%

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Febbo

et al. 2007

The American Journal of Pathology

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“…16 Kyprianou's group has shown loss of p27 in prostatic carcinoma as well as the important observation that this loss is associated with higher proliferative activity and higher tumor grade. 17 Cordon-Cardo et al 18 have demonstrated loss of p27 in prostatic carcinoma, as well as diffuse p27 staining in normal prostate epithelium and a distinct absence of staining in BPH nodules.…”

Section: Discussionmentioning

confidence: 97%

“…20 While approximately one-third of our patients showed decreased staining for p27 in hyperplasia, the effect was more prominent in defined nodules (43%), which is consistent with the findings of other investigators. 18 The process of apoptosis protects the integrity of the genome by eliminating cells with extensive DNA damage or those undergoing uncontrolled proliferation. 11 For instance, during development, RB knockout mice did not experience uncontrolled cellular growth as expected because apoptotic processes eliminated abnormally cycling cells.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of apoptotic and cell cycle regulatory proteins in distinct histopathologic components of benign prostatic hyperplasia

Gandour‐Edwards

Mack

DeVere-White

et al. 2004

Prostate Cancer Prostatic Dis

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Introduction: Benign prostatic hyperplasia (BPH) is a slowly progressive abnormal glandular enlargement with heterogeneous morphology. Disruption of apoptotic pathways has been suggested as an important regulatory mechanism in this common and significantly morbid disease. Methods: Prostatic tissue from 20 patients with BPH and no prior or subsequent prostatic carcinoma was obtained by transurethral prostatectomy (TURP) at the University of California Davis. Apoptotic regulatory proteins: BCL2, BAX and p27 were analyzed by immunohistochemistry and evaluated for expression in four distinct histologic patterns: hyperplastic epithelium, nodules, dilated glands and atrophic/inflammatory glands. Results: Particularly striking was the decreased expression of BAX and an abnormal BCL2 : BAX ratio within all nodules relative to expression in other epithelial patterns. p27 expression was decreased in 35% of the hyperplastic epithelial areas and 10% of the nodules. Discussion: Overall, abnormal expression of BCL2, BAX and/or p27 was identified in the hyperplastic epithelium of 19 (90%) of specimens and all 12 (100%) of the hyperplastic nodules. The high frequency of abnormalities in apoptosis regulatory genes, suggests that alteration of apoptotic pathways is important for the development of this condition.

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“…The p27 Kip1 protein expression is decreased in a number of tumor types, including breast, colon, prostate and ovarian tumors (Catzevalos et al, 1997;Ciaparrone et al, 1998;Cordon-Cardo et al, 1998;Masciullo et al, 1999). Conversely in BRCA1 knockout mouse models, reduction of BRCA1 is accompanied by an increase in the expression of p27 Kip1 at the mRNA and protein levels (Brodie et al, 2001;Deans et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

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We have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27 Kip1 promoter. The BRCA1-responsive element was defined as a 35 bp region from position À545 to À511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27 Kip1 promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27 Kip1 promoter. Mutation of the FOXA1 DNA-binding site in the p27 Kip1 promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27 Kip1 promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27 Kip1 promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27 Kip1 promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27 Kip1 transcription and a possible interaction with BRCA1.

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Distinct Altered Patterns of p27KIP1 Gene Expression in Benign Prostatic Hyperplasia and Prostatic Carcinoma

Abstract: On the basis of these results, we infer that loss of p27Kip1 expression in the human prostate may be causally linked to BPH and that BPH is not a precursor to prostate cancer.

Cited by 267 publications

References 43 publications

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Stromally Expressed c-Jun Regulates Proliferation of Prostate Epithelial Cells

Abnormalities of apoptotic and cell cycle regulatory proteins in distinct histopathologic components of benign prostatic hyperplasia

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

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