-
Whitney K Hendrickson,
Richard Flavin,
Julie L Kasperzyk,
Michelangelo Fiorentino,
Fang Fang, Rosina Lis,
Christopher Fiore,
Kathryn L Penney,
Jing Ma,
Philip W Kantoff,
Meir J Stampfer,
Massimo Loda,
Lorelei A Mucci,
Edward Giovannucci
[show abstract]
[hide abstract]
ABSTRACT: Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies.
We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI.
Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression.
High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.
Journal of Clinical Oncology 06/2011; 29(17):2378-85. · 18.37 Impact Factor
-
Anna R Laury,
Ruth Perets,
Huiying Piao,
Jeffrey F Krane,
Justine A Barletta,
Christopher French,
Lucian R Chirieac, Rosina Lis,
Massimo Loda,
Jason L Hornick,
Ronny Drapkin,
Michelle S Hirsch
[show abstract]
[hide abstract]
ABSTRACT: PAX8 is a paired-box gene important in embryogenesis of the thyroid, Müllerian, and renal/upper urinary tracts, and expression of PAX8 has been previously described in carcinomas from each of these sites. However, a large study including a wide variety of epithelial neoplasms from multiple organ sites other than the thyroid, kidney, or Müllerian system has not been performed. The goal of this study was to evaluate the utility of PAX8 immunostaining based on the evaluation of a wide range of epithelial tumors. PAX8 immunohistochemistry was performed on 1357 tumors (486 tumors in whole-tissue sections and 871 tumors in tissue microarrays, predominantly epithelial) from multiple organs. Only nuclear staining was scored as positive, and tumors were evaluated for the extent and intensity of staining. Western blot analysis with PAX8 was also performed on multiple tumor cell lines. Nuclear PAX8 staining was present in 91% (60 of 66) of thyroid tumors, 90% (158 of 176) of renal cell carcinomas (RCCs), 81% (13 of 16) of renal oncocytomas, 99% (164 of 165) of high-grade ovarian serous carcinomas, 71% (32 of 49) of nonserous ovarian epithelial neoplasms, 91% (10 of 11) of cervical epithelial lesions, and 98% (152 of 155) of endometrial adenocarcinomas. Of the remaining 719 evaluated tumors, only 30 cases (4%), including 12 thymic neoplasms, 3 bladder urothelial carcinomas, 4 lung squamous cell carcinomas, 2 esophageal adenocarcinomas, 1 pancreatic adenocarcinoma, 2 cholangiocarcinomas, 1 ovarian Sertoli-Leydig cell tumor, 1 ovarian sex cord stromal tumor, 3 testicular mixed germ cell tumors, and 1 acinic cell carcinoma, showed at least weak or focal PAX8 positivity. The unexpected finding was diffuse, moderate staining of PAX8 in a subset of thymomas and thymic carcinomas. The 689 remaining tumors, including but not limited to those from the prostate, colon, stomach, liver, adrenal gland, and head and neck, and small cell carcinomas from the lung, cervix, and ovary, were PAX8 negative. PAX8 specificity was confirmed by Western blot analysis, as expression was detected only in ovarian and RCC cell lines. These results show that PAX8 is a highly sensitive marker for thyroid, renal, Müllerian, and thymic tumors. Importantly, all lung adenocarcinomas, breast and adrenal neoplasms, and the majority of gastrointestinal tumors were negative for PAX8. Therefore, PAX8 is an excellent marker for confirming primary tumor site. In a subset of cases, additional markers, including but not limited to thyroid transcription factor-1, RCC, and Wilms tumor-1, may be needed to distinguish between the 3 most common PAX8-positive tumors.
The American journal of surgical pathology 06/2011; 35(6):816-26. · 4.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: TRAIL (tumor necrosis factor related apoptosis-inducing ligand) is involved in tumor immune surveillance and, thus, may be a potential cancer therapy. TRAIL expression in the tumor microenvironment has been shown to impact cancer survival in multiple tumor types, including ovarian cancer. We studied TRAIL expression and outcomes in patients with prostate cancer.
A tissue microarray (TMA) of 200 prostate cancer patients and benign prostate tissue controls was used to assess the epithelial and stromal protein expression of TRAIL, death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and the FLICE inhibitory protein (FLIP(L) ). We correlated these expression patterns with clinicopathological parameters and determined its impact on recurrence-free survival.
Nearly all (99.5%) prostate cancer tissues examined displayed either decreased expression of pro-apoptotic TRAIL receptors, increased FLIP(L) expression, or both. We observed elevated death receptor, decoy receptor, FLIP(L) , and epithelial TRAIL expression in prostate cancer epithelium. TRAIL expression in the stromal tumor microenvironment surrounding the prostate cancer was markedly lower. Elevated TRAIL expression in the tumor microenvironment was also significantly associated with increased recurrence-free survival (P = .014), after controlling for other prognostic markers. In contrast, epithelial expression of TRAIL did not have an effect on overall survival.
Expression of the components of the pro-apoptotic TRAIL pathway is altered in prostate cancer. Moreover, TRAIL expression in the tumor microenvironment may affect recurrence-free survival rate of prostate cancer patients. Consequently, these results may be useful in devising future therapeutic strategies targeting the TRAIL pathway in prostate cancer.
Cancer 03/2011; 117(6):1172-82. · 4.77 Impact Factor
-
Zhihu Ding,
Chang-Jiun Wu,
Gerald C Chu,
Yonghong Xiao,
Dennis Ho,
Jingfang Zhang,
Samuel R Perry,
Emma S Labrot,
Xiaoqiu Wu, Rosina Lis, [......],
Nabeel Bardeesy,
Y Alan Wang,
David E Hill,
Todd R Golub,
Meir J Stampfer,
Wing H Wong,
Massimo Loda,
Lorelei Mucci,
Lynda Chin,
Ronald A DePinho
[show abstract]
[hide abstract]
ABSTRACT: Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.
Nature 02/2011; 470(7333):269-73. · 36.28 Impact Factor
-
Paul L Nguyen,
Jing Ma,
Jorge E Chavarro,
Matthew L Freedman, Rosina Lis,
Giuseppe Fedele,
Christopher Fiore,
Weiliang Qiu,
Michelangelo Fiorentino,
Stephen Finn,
Kathryn L Penney,
Anna Eisenstein,
Fredrick R Schumacher,
Lorelei A Mucci,
Meir J Stampfer,
Edward Giovannucci,
Massimo Loda
[show abstract]
[hide abstract]
ABSTRACT: Fatty acid synthase (FASN) regulates de novo lipogenesis, body weight, and tumor growth. We examined whether common germline single nucleotide polymorphisms (SNPs) in the FASN gene affect prostate cancer (PCa) risk or PCa-specific mortality and whether these effects vary by body mass index (BMI).
In a prospective nested case-control study of 1,331 white patients with PCa and 1,267 age-matched controls, we examined associations of five common SNPs within FASN (and 5 kb upstream/downstream, R(2) > 0.8) with PCa incidence and, among patients, PCa-specific death and tested for an interaction with BMI. Survival analyses were repeated for tumor FASN expression (n = 909).
Four of the five SNPs were associated with lethal PCa. SNP rs1127678 was significantly related to higher BMI and interacted with BMI for both PCa risk (P(interaction) = .004) and PCa mortality (P(interaction) = .056). Among overweight men (BMI > or = 25 kg/m(2)), but not leaner men, the homozygous variant allele carried a relative risk of advanced PCa of 2.49 (95% CI, 1.00 to 6.23) compared with lean men with the wild type. Overweight patients carrying the variant allele had a 2.04 (95% CI, 1.31 to 3.17) times higher risk of PCa mortality. Similarly, overweight patients with elevated tumor FASN expression had a 2.73 (95% CI, 1.05 to 7.08) times higher risk of lethal PCa (P(interaction) = .02).
FASN germline polymorphisms were significantly associated with risk of lethal PCa. Significant interactions of BMI with FASN polymorphisms and FASN tumor expression suggest FASN as a potential link between obesity and poor PCa outcome and raise the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men.
Journal of Clinical Oncology 09/2010; 28(25):3958-64. · 18.37 Impact Factor
