Glutathione S-Transferase Pi (Gstp1) Deficiency Accelerates Prostate Carcinogenesis in the Lo-Myc Mouse

Iwata, Takashi; Schultz, Denise; Vaughn, Matthew; Yegnasubramanian, Srinivasan; Nelson, William G.; Marzo, Angelo M. De

doi:10.1016/s0022-5347(09)60528-0

Cited by 3 publications

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“…The functional significance of GSTP1 silencing in prostate cancer is still under study, but one example is that it may be involved in protection against cytotoxicity and DNA adduct formation occurring in the setting of exposure to charred meat carcinogens [71] , and others suggest a role as a tumor suppressor after carcinogen exposure in skin and lung cancer models [72] , [73] . We have preliminary evidence for a role of GSTP1 as a bone fide tumor suppressor in prostate cancer [74] , and, using a newly updated IHC assay have provided strong evidence that normal prostatic luminal epithelial cells in human express GSTP1, albeit at much lower levels than normal basal cells or atrophic cells [42] . Since the target cell for prostate cancer initiation appears to be a luminal epithelial cell, these new results provide additional insights into the earliest steps in human prostate cancer formation.…”

Section: Examples Of Ihc Assays and Insights They Have Facilitatedmentioning

confidence: 99%

If this is true, what does it imply? How end-user antibody validation facilitates insights into biology and disease

Sfanos

Yegnasubramanian

Nelson

et al. 2019

Asian Journal of Urology

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Antibodies are employed ubiquitously in biomedical sciences, including for diagnostics and therapeutics. One of the most important uses is for immunohistochemical (IHC) staining, a process that has been improving and evolving over decades. IHC is useful when properly employed, yet misuse of the method is widespread and contributes to the “reproducibility crisis” in science. We report some of the common problems encountered with IHC assays, and direct readers to a wealth of literature documenting and providing some solutions to this problem. We also describe a series of vignettes that include our approach to analytical validation of antibodies and IHC assays that have facilitated a number of biological insights into prostate cancer and the refutation of a controversial association of a viral etiology in gliomas. We postulate that a great deal of the problem with lack of accuracy in IHC assays stems from the lack of awareness by researchers for the critical necessity for end-users to validate IHC antibodies and assays in their laboratories, regardless of manufacturer claims or past publications. We suggest that one reason for the pervasive lack of end-user validation for research antibodies is that researchers fail to realize that there are two general classes of antibodies employed in IHC. First, there are antibodies that are “clinical grade” reagents used by pathologists to help render diagnoses that influence patient treatment. Such diagnostic antibodies, which tend to be highly validated prior to clinical implementation, are in the vast minority (e.g. < 500). The other main class of antibodies are “research grade” antibodies (now numbering >3 800 000), which are often not extensively validated prior to commercialization. Given increased awareness of the problem, both the United States, National Institutes of Health and some journals are requiring investigators to provide evidence of specificity of their antibody-based assays.

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Section: Examples Of Ihc Assays and Insights They Have Facilitatedmentioning

confidence: 99%

If this is true, what does it imply? How end-user antibody validation facilitates insights into biology and disease

Sfanos

Yegnasubramanian

Nelson

et al. 2019

Asian Journal of Urology

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“…The functional significance of GSTP1 silencing in prostate cancer is still under study, but one example is that it may be involved in protection against cytotoxicity and DNA adduct formation occurring in the setting of exposure to charred meat carcinogens (Nelson et al 2001). In recent work that is still in process, it appears that in the right context, mouse Gstp1/2 (the equivalent of human GSTP1 is mouse Gstp1/2, which has two tandem copies of the gene) may function as an overt tumor suppressor in prostate cancer (Iwata et al 2009) because crosses of mice with forced activation of MYC in the prostate to mice lacking Gstp1/2 resulted in increased tumorigenesis (Iwata et al 2009).…”

Section: Key Molecular Pathway Alterations Accompanying the Developme...mentioning

confidence: 99%

Molecular Pathology of High-Grade Prostatic Intraepithelial Neoplasia: Challenges and Opportunities

Trabzonlu

Kulaç

Zheng

et al. 2018

Cold Spring Harb Perspect Med

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A better understanding of the early stages of prostate cancer initiation, potentially arising from precursor lesions, may fuel development of powerful approaches for prostate cancer prevention or interception. The best-known candidate for such a precursor lesion has been referred to as high-grade prostatic intraepithelial neoplasia (HGPIN). Although there is significant evidence supporting the notion that such HGPIN lesions can give rise to invasive adenocarcinomas of the prostate, there are also numerous complicating considerations and evidence that cloud the picture in many instances. Notably, recent evidence has suggested that some fraction of such lesions that are morphologically consistent with HGPIN may actually be invasive carcinomas masquerading as HGPIN-a state that we term "postinvasive intraepithelial carcinoma" (PIC). Although the prevalence of such PIC lesions is not fully understood, this and other factors can confound the potential of identifying prostate precursors that can be targeted for disease prevention, interception, or treatment. Here, we review our current understanding of the morphological and molecular pathological features of prostate cancer precursor lesions.

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“…In mouse models of carcinogen exposure induced cancers of the lung and skin, Gstp1/2 behaves as a tumor suppressor [ 10 , 11 ]. In a mouse model of early prostate cancer development induced by human MYC, Gstp1/2 also functions as a tumor suppressor [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States

et al. 2021

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GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90–95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). In terms of association with other molecular alterations, GSTP1 positivity was enriched in ERG positive cancers among Black men. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTP1-positive tumor cells. This is the first report revealing that GSTP1-positive prostate cancers are substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men.

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Glutathione S-Transferase Pi (Gstp1) Deficiency Accelerates Prostate Carcinogenesis in the Lo-Myc Mouse

Cited by 3 publications

References 0 publications

If this is true, what does it imply? How end-user antibody validation facilitates insights into biology and disease

If this is true, what does it imply? How end-user antibody validation facilitates insights into biology and disease

Molecular Pathology of High-Grade Prostatic Intraepithelial Neoplasia: Challenges and Opportunities

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States

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