Reduced MLH1  Expression in Breast Tumors After  Primary Chemotherapy Predicts Disease-Free  Survival

Mackay, Helen; Cameron, David; Rahilly, Maeve A.; Mackean, Melanie; Paul, Jim; Kaye, SB; Brown, Robert E.

doi:10.1200/jco.2000.18.1.87

Cited by 88 publications

(65 citation statements)

References 30 publications

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“…Indeed, very recently it was demonstrated in paired breast cancer samples obtained before and after chemotherapy that doxorubicin-based chemotherapy resulted in a significant reduction of cells expressing MLH1. 37 Although these results should be viewed with caution because of the very small patient number and different chemotherapy regimens, the data are consistent with the hypothesis that tumor cells with reduced MLH1 have a survival advantage during doxorubicin-based chemotherapy.…”

Section: Discussionsupporting

confidence: 78%

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repairdeficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poisonmediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.

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Section: Discussionsupporting

confidence: 78%

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

et al. 2001

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“…We and others (Brown et al, 1997;Fink et al, 1998a;Samimi et al, 2000) have shown that there is an increase in the number of ovarian tumour cells that score negative for MLH1 expression following platinum-based chemotherapy when compared with untreated tumours. Recently, studies have correlated tumour response and poor disease-free survival with loss of MLH1 expression in breast cancer tumours following anthracycline-based neoadjuvant chemotherapy (Mackay et al, 2000). These observations support the concept of in vivo enrichment of a subpopulation of MMRdeficient cells in response to treatment, which are more likely to be drug resistant, have a mutator phenotype and consequently, an adverse effect on prognosis.…”

Section: Discussionmentioning

confidence: 65%

Photodynamic therapy of DNA mismatch repair-deficient and -proficient tumour cells

et al. 2002

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Loss of DNA mismatch repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumours. DNA mismatch repair-deficient cells have been reported to be resistant to many chemotherapeutic agents and to radiotherapy, and to have the potential of rapidly acquiring additional mutations leading to tumour progression. Photodynamic therapy is a new treatment modality using light to activate a photosensitiser that preferentially localises in tumour cells. An oxygen dependent photochemical reaction ensues, resulting in selective tumour necrosis. The effect of loss of DNA mismatch repair activity on the sensitivity to photodynamic therapy was tested using pairs of cell lines proficient or deficient in mismatch repair due to loss of either MLH1 or MSH2 protein function. Cells were incubated with the photosensitiser 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin and exposed to laser light at 652 nm with various optical doses ranging from 0 -1 J cm 72 . Cell survival was assessed using the clonogenic assay. Loss of MLH1 or MSH2 function was not associated with resistance to photodynamic therapy. MCF-7 cells repeatedly treated with photodynamic therapy expressed parental levels of MLH1, MSH2, MSH6, and PMS2. DNA mismatch repair-deficient and -proficient cells showed similar subcellular distributions of meta-tetra(hydroxyphenyl)chlorin as analysed by laser scanning and fluorescence microscopy. Therefore, repeated exposure of tumour cells to photodynamic therapy does not seem to result in loss of DNA mismatch repair, and loss of mismatch repair, in turn, does not seem to contribute to resistance to photodynamic therapy. Our results suggest recommending photodynamic therapy as a strategy for circumventing resistance due to loss of DNA mismatch repair.

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“…The catalyst for these studies has been the knowledge that a majority of sporadic tumors with loss of mismatch repair (MMR) are deficient in MLH1 in association with hypermethylation of the promoter region. Clinically, several studies have reported correlations between hMLH1 expression and drug resistance or prior therapy (Strathdee et al, 1999;Mackay et al, 2000). In vitro, loss of MMR proficiency results in resistance to DNA-damaging agents including cisplatin and doxorubicin, suggesting that for some drugs, MMR proteins may provide the link between DNA damage and the activation of apoptosis (Aebi et al, 1997;Brown et al, 1997;Plumb et al, 2000).…”

Section: Modulating Methylation Status To Regulate Drug Sensitivitymentioning

confidence: 99%