Expression of the multidrug resistance-associated protein (MRP) gene in colorectal carcinomas

Fillpits, M; Suchomel, Ralf W.; Dekan, Gerhard; Stiglbauer, Wolfgang; Haider, Karin; Depisch, D.; Pirker, Robert

doi:10.1038/bjc.1997.35

Cited by 35 publications

(38 citation statements)

References 27 publications

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“…No correlation was found in the study by Nooter et al (1997a): MRP1 was found to be expressed in 23/76 (30%) T1, 50/148 (34%) T2, and in 12/33 (36%) T3 tumors. Filipits et al (1999) observed no significant difference in T stage distribution between 20 MRP1 − and 80 MRP1 + primary breast cancer patients. However, MRP1 was detected more often in operable primary (16/20) than in locally advanced cancers (two of ten before neoadjuvant treatment) in the study by Linn et al (1997).…”

Section: Expression In Normal Breast and In Breast Cancer Effect Of mentioning

confidence: 63%

“…No correlation was observed between MRP1 protein (Nooter et al 1997a, Filipits et al 1999 or mRNA (Lacave et al 1998, Kanzaki et al 2001 lesion and lymph node status. Zochbauer- Muller et al (2001) observed a higher MRP1 protein staining intensity in lymph nodes than in their corresponding primary tumors.…”

Section: Expression In Normal Breast and In Breast Cancer Effect Of mentioning

confidence: 99%

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ATP binding cassette transporters and drug resistance in breast cancer.

Leonessa¹,

Clarke²

2003

Endocrine-Related Cancer

233

178

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Resistance to chemotherapy is a critical issue in the management of breast cancer patients. The nature of clinical drug resistance is likely to be multifactorial. However, in the last decade considerable attention has been dedicated to the role played by membrane transporter proteins belonging to the ATP binding cassette protein superfamily, and in particular by the MDR1 product P-glycoprotein (Pgp) and the multidrug resistance protein (MRP1). Heterogeneity of results is a common feature of studies evaluating the expression and prognostic role of these proteins, due to both methodological and biological factors. Nonetheless, Pgp and MRP1 are detected in a significant proportion of untreated breast cancers (on average 40 and 50% respectively, by immunohistochemistry), without a clear and consistent association with cancer stage. Exposure to chemotherapy increases the expression of both proteins. In vitro studies on primary cultures of breast cancer cells obtained at surgery consistently show an association between Pgp (protein) or MDR1 (mRNA) expression and resistance to chemotherapy. However, the correlation with clinical drug resistance is not as well defined. A stronger association of Pgp/MDR1 with response rates has been observed when expression or an increase in expression are detected immediately following chemotherapy. Correlations with prognosis appear more evident in studies using immunohistochemistry, in adjuvant and neoadjuvant settings. Evidence of clinical reversal of drug resistance by verapamil suggests a functional role of Pgp in drug resistance, although the significance of the evidence is generally weakened by poor trial designs. Future studies should take into account the multifactorial nature of drug resistance in breast cancer and use standardized approaches with adequate controls. Expression studies should be complemented by well-designed trials of drug-resistance reversal using target-specific chemosensitizing agents, and relating the results to the levels of expression of the target proteins.

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Section: Expression In Normal Breast and In Breast Cancer Effect Of mentioning

confidence: 63%

Section: Expression In Normal Breast and In Breast Cancer Effect Of mentioning

confidence: 99%

ATP binding cassette transporters and drug resistance in breast cancer.

Leonessa¹,

Clarke²

2003

Endocrine-Related Cancer

233

178

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“…For example, the expressions and activities of the well characterized P-glycoprotein (Kartner et al, 1986) and the multidrug resistance-associated protein (MRP) (Cole et al, 1992) have been described in leukemia, small cell lung cancer, retinoblastoma and colorectal carcinoma, among others (Legrand et al, 1998;Chan et al, 1997;Fillpits et al, 1997). The expression of TYRP2, on the other hand, has been shown to be limited to cells of melanocytic lineage in normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications

et al. 2000

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A major obstacle in the systemic treatment of advanced malignant melanoma is its intrinsic resistance to conventionally used chemotherapeutic agents. In order to investigate the mechanisms of this intrinsic resistance, we have previously utilized retroviral insertional mutagenesis on an early-stage, drug sensitive human melanoma cell line (WM35) to establish mutated cell lines that exhibited increased resistance to cis-diamminedichloroplatinum(II) (CDDP). Here, we demonstrate that this increased resistance to CDDP is mediated by the over-expression of tyrosinase-related protein-2 (TYRP2), an enzyme that normally functions in the biosynthesis of the pigment, melanin. Northern and Western blot analyses revealed that the expression of TYRP2 in the virally-derived cell lines as well as in a panel of human melanoma cell lines positively correlated with their levels of resistance to CDDP. Furthermore, enforced expression of TYRP2 in WM35 cells by transfection elevated their resistance to CDDP. The increased CDDP resistance in the virally-derived clones and TYRP2 transfectants was accompanied by a reduction in CDDP-induced apoptosis. Interestingly, the virally-derived CDDP-resistant clones also showed cross resistance to carboplatin and methotrexate, but not taxol, suggesting that TYRP2 over-expression may confer resistance speci®cally to DNA damaging agents.Overall, these results demonstrate a novel mechanism of drug resistance in human melanoma cells that is mediated by the over-expression of TYRP2. Since TYRP2 is expressed only in cells of melanocytic lineage, this may represent the ®rst report of a lineage-speci®c mechanism of drug resistance. In summary, these ®ndings suggest a signi®cant role for TYRP2 in the intrinsic drug resistance phenotype of human melanoma cells and may have important implications in the development of chemosensitization strategies for the clinical management of this disease. Oncogene (2000) 19, 395 ± 402.

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“…Overexpression of membrane pumps that extrude a wide range of anticancer drugs (Filipits et al 1999) could explain the different efficacy of HDAC inhibitors in ER+ and ER breast cancer cells. We therefore wanted to eliminate the possibility that the resistance of ER breast cancer cells to HDAC inhibitors could be caused by an increase of the general multidrug resistance (MDR) phenotype.…”

Section: Er Breast Cancer Cells Are Less Sensitive To Hdac Inhibitionmentioning

confidence: 99%

Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells

Margueron¹,

Licznar²,

Lazennec³

et al. 2003

Journal of Endocrinology

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We analysed the antiproliferative activity of various histone deacetylase (HDAC) inhibitors such as trichostatin A (TSA) on human breast cancer cells. We observed a lower sensitivity to HDAC inhibition for oestrogen receptor negative (ER ) versus positive (ER+) cell lines. This differential response was associated neither with a modification of drug efflux via the multidrug resistance system nor with a global modification of histone acetyltransferase (HAT)/HDAC activities. In contrast, we demonstrated that in ER+ breast cancer cells the p21 WAF1/CIP1 gene was more sensitive to TSA regulation and was expressed at higher levels. These differences were observed both in transient transfection experiments and on the endogenous p21 WAF1/CIP1 gene. The Sp1 transcription factor, which was shown to interact in vitro with both class I and class II HDACs, is sufficient to confer the differential sensitivity to TSA and participated in the control of p21 WAF1/CIP1 basal expression. Finally, re-expression of ER following adenoviral infection of ER breast cancer cells increased both p21WAF1/CIP1 protein accumulation and the growth inhibitory activity of TSA. Altogether, our results highlight the key role of ER and p21 WAF1/CIP1 gene expression in the sensitivity of breast cancer cells to hyperacetylating agents.

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Expression of the multidrug resistance-associated protein (MRP) gene in colorectal carcinomas

Cited by 35 publications

References 27 publications

ATP binding cassette transporters and drug resistance in breast cancer.

ATP binding cassette transporters and drug resistance in breast cancer.

Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications

Oestrogen receptor alpha increases p21(WAF1/CIP1) gene expression and the antiproliferative activity of histone deacetylase inhibitors in human breast cancer cells

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