Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light

Meyer, Karen M; Hess, Stephen; Tlsty, Thea D.; Leadon, Steven A.

doi:10.1038/sj.onc.1202977

Cited by 33 publications

(26 citation statements)

References 46 publications

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“…All four of our cell lines are wild type for p53 by sequence analysis and express p53 protein (data not shown); therefore, the differences in p21 waf1 expression cannot be attributed to differences in p53 status. p21 waf1 is involved in the G 1 checkpoint response, and others have reported an impaired G 1 checkpoint in HME cell lines (34). Consistent with a strong cell cycle checkpoint in the luminal cell lines, MCF-7 and ZR-75-1 cells also repressed a large set of proliferation genes (Fig.…”

Section: Discussionsupporting

confidence: 54%

Cell-Type-Specific Responses to Chemotherapeutics in Breast Cancer

et al. 2004

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Recent microarray studies have identified distinct subtypes of breast tumors that arise from different cell types and that show statistically significant differences in patient outcome. To gain insight into these differences, we identified in vitro and in vivo changes in gene expression induced by chemotherapeutics. We treated two cell lines derived from basal epithelium (immortalized human mammary epithelial cells) and two lines derived from luminal epithelium (MCF-7 and ZR-75-1) with chemotherapeutics used in the treatment of breast cancer and assayed for changes in gene expression using DNA microarrays. Treatment doses for doxorubicin and 5-fluorouracil were selected to cause comparable cytotoxicity across all four cell lines. The dominant expression response in each of the cell lines was a general stress response; however, distinct expression patterns were observed. Both cell types induced DNA damageresponse genes such as p21 waf1 , but the response in the luminal cells showed higher fold changes and included more p53-regulated genes. Luminal cell lines repressed a large number of cell cycle-regulated genes and other genes involved in cellular proliferation, whereas the basal cell lines did not. Instead, the basal cell lines repressed genes that were involved in differentiation. These in vitro responses were compared with expression responses in breast tumors sampled before and after treatment with doxorubicin or 5-fluorouracil/mitomycin C. The in vivo data corroborated the cell-type-specific responses to chemotherapeutics observed in vitro, including the induction of p21 waf1 . Similarities between in vivo and in vitro responses help to identify important response mechanisms to chemotherapeutics.

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Section: Discussionsupporting

confidence: 54%

Cell-Type-Specific Responses to Chemotherapeutics in Breast Cancer

et al. 2004

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“…In our cell lines, p53 genes were found to be mutated and the function of p53 was found to be absent in yeast assays. Despite this, we found that the UPN1 exhibited a G2 cell cycle arrest and underwent apoptosis, as this has usually been reported after irradiation (Iavarone and Massague, 1997;Meyer et al, 1999). In our study, UPN2 cell line underwent Sphase arrest after irradiation.…”

Section: Discussionmentioning

confidence: 36%

“…These checkpoints are also activated in response to DNA damage to allow time for repair and to maintain stability of the genome. The importance of p53 in the activation of the G1/S checkpoint after irradiation have been well established (Meyer et al, 1999). This event therefore requires the presence of normal levels of a functional p53 protein, which can then activate its target gene at the transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma

et al. 2003

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Mantle cell lymphomas (MCL) are characterized by their aggressive behavior and poor response to chemotherapy regimens. We report here evidence of increased in vitro radiation sensitivity in two cell lines that we have generated from two MCL patients (UPN1 and UPN2). However, despite their increased radiation sensitivity, UPN2 cells were totally resistant to apoptotic cell death, whereas UPN1 cells underwent massive apoptosis 6 h after irradiation. The frequency of induced chromosomal abnormalities was higher in UPN1 as compared to UPN2. Distinct mechanisms have been found to contribute to this phenotype: a major telomere shortening (UPN1 and UPN2), deletion of one ATM allele and a point mutation in the remaining allele in UPN2, mutation of p53 gene (UPN1 and UPN2) with absence of functional p53 as revealed by functional yeast assays. After irradiation, Ku70 levels in UPN1 increased and decreased in UPN2, whereas in the same conditions, DNA-PKcs protein levels decreased in UPN1 and remained unchanged in UPN2. Thus, irradiation-induced apoptotic cell death can occur despite the nonfunctional status of p53 (UPN1), suggesting activation of a unique pathway in MCL cells for the induction of this event. Overall, our study demonstrates that MCL cells show increased radiation sensitivity, which can be the result of distinct molecular events. These findings could clinically be exploited to increase the dismal response rates of MCL patients to the current chemotherapy regimens.

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“…As in many other types of normal human epithelial cells (Flatt et al 1998, Meyer et al 1999, p53 activation by DNA-damaging agents is attenuated in primary cultures of normal prostatic epithelial cells (Girinsky et al 1995, Bromfield et al 2003. This attenuation has been attributed to a need for progenitor or stem-like cells to repress p53 activity so as not to self-eliminate through p53-mediated apoptosis (Dumble et al 2001).…”

Section: Tumor Suppressorsmentioning

confidence: 99%

Primary cell cultures as models of prostate cancer development

Peehl¹

2005

Endocr Relat Cancer

152

142

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This review focuses on primary cultures of human prostatic epithelial cells and their applications as models of normal and malignant biological behavior. Current abilities to culture cells from normal tissues, from premalignant dysplastic lesions (prostatic intraepithelial neoplasia), from primary adenocarcinomas, and from metastases are described. Evidence for representation of the interrelated cells of the normal prostatic epithelium -stem cells, basal epithelial cells, secretory epithelial cells, transit amplifying cells and neuroendocrine cells -in primary cultures is presented. Comparisons between normal and cancer-derived primary cultures are made regarding biological activities relevant to carcinogenesis, such as proliferation, apoptosis, differentiation, senescence, adhesion, migration, invasion, steroid hormone metabolism, other metabolic pathways and angiogenesis. Analyses of tumor suppressor activity, differential gene expression and cytogenetics in primary cultures have revealed changes relevant to prostate cancer progression. Preclinical studies with primary cultures have provided information useful for designing new strategies for chemoprevention, chemotherapy, cytotoxin therapy, radiation therapy, gene therapy and imaging. While the behavior of normal primary cultures is often used as a basis for comparison with established, immortal prostate cancer cell lines, the most informative studies are performed with donor-matched pairs of normal and malignant primary cultures, grown under identical conditions. Challenges that remain to be addressed if the full potential of primary cultures as a model system is to be realized include isolation, culture and characterization of stem cells, improved methodology to induce or maintain a fully differentiated, androgen-responsive phenotype, and identification of cell surface antigens or other markers with which to purify pure populations of live cancer or premalignant cells apart from non-malignant epithelial cells prior to culture.

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Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light

Cited by 33 publications

References 46 publications

Cell-Type-Specific Responses to Chemotherapeutics in Breast Cancer

Cell-Type-Specific Responses to Chemotherapeutics in Breast Cancer

Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma

Primary cell cultures as models of prostate cancer development

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