Biomedical subjects
Ramon Parsons
Publications and source records attributed to Ramon Parsons.
HLTF gene silencing in human colon cancer.
Chromatin remodeling enzymes are increasingly implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, have been shown to be disrupted in cancer. In this study we identified as a target for gene inactivation in colon cancer the gene for helicase-like transcription factor (HLTF), a SWI/SNF family protein. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in nine of 34 colon cancer cell lines. In these cell lines HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colony growth in each of three different HLTF-deficient cell lines, but showed no suppressive effect in any of three HLTF-proficient cell lines. These findings show that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggest HLTF is a candidate colon cancer suppressor gene.
Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis.
Mouse models have provided significant insights into the molecular mechanisms of tumor suppressor gene function. Here we use mouse models of prostate carcinogenesis to demonstrate that the Nkx3.1 homeobox gene undergoes epigenetic inactivation through loss of protein expression. Loss of function of Nkx3.1 in mice cooperates with loss of function of the Pten tumor suppressor gene in cancer progression. This cooperativity results in the synergistic activation of Akt (protein kinase B), a key modulator of cell growth and survival. Our findings underscore the significance of interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten in contributing to the distinct phenotypes of different cancers.
Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice.
Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.
DNA mismatch repair deficiency accelerates endometrial tumorigenesis in Pten heterozygous mice.
PTEN mutation and microsatellite instability are two of the most common genetic alterations in uterine endometrioid carcinoma. Furthermore, previous studies have suggested an association between the two alterations, however the basis and consequence of the association is not understood. Recently it has been shown that 100% of female Pten(+/-) mice develop complex atypical hyperplasia by 32 weeks of age that progresses to endometrial carcinoma in approximately 20 to 25% of mice at 40 weeks. In an attempt to expand this mouse model of endometrial tumorigenesis and to further our understanding of the association betweenPten mutations and DNA mismatch repair deficiency, we generated Ptenheterozygous, Mlh1-null (mismatch repair deficient) mice. Significantly, the majority ofPten(+/-)/Mlh1(-/-)mice developed polypoid lesions in the endometrium at 6 to 9 weeks of age. By 14 to 18 weeks, all of the double-mutant mice had lesions histologically similar to those seen inPten(+/-) mice, and two of them exhibited invasive disease. Moreover, the frequency of loss of the wild-type Pten allele in the double-mutant mice at 14 to 18 weeks was similar to that seen in lesions from 40-week-old Pten(+/-) mice. Taken together, our results indicate that DNA mismatch repair deficiency can accelerate endometrial tumorigenesis inPten heterozygous mice and suggests that loss of the wild-type Pten allele is involved in the development/progression of tumors in this setting.
Reduced expression of PTEN correlates with breast cancer progression.
PTEN is a tumor-suppressor gene with phosphatase activity that is mutated in a variety of cancers. We analyzed a series of 34 invasive and 18 in situ breast cancers with known molecular status of the PTEN genotype using immunohistochemistry. Reduced PTEN protein expression was seen in 38% of invasive cancers and in 11% of in situ cancers. The frequency of reduced expression was highest in stage II and III cancers. Reduced expression also correlated with aneuploidy. In addition, in tumors with both in situ and invasive components, expression within the ductal carcinoma in situ portion tended to reflect the expression pattern of the invasive component. These data suggest that PTEN expression is frequently reduced in advanced breast cancers.