MDR1 gene expression in primary and advanced breast cancer
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1Norris Comprehensive Cancer Center, Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Abstract:
P-glycoprotein (Pgp)-associated multidrug resistance (MDR) is related to intrinsic and acquired cross resistance to anthracyclines, vinca alkaloids, and other antineoplastic antibiotics. Expression of MDR1 is widely considered to play an important role in conferring resistance to adjuvant chemotherapy in women with breast tumor cells in women with disseminated disease, although data supporting this view is, at best, conflicting. The expression of MDR1 gene and its gene product, P-glycoprotein, was investigated in primary and advanced breast cancers (both previously untreated and previously treated on specific treatment protocols) to assess the role of P-glycoprotein in determining responsiveness to adjuvant chemotherapy. Expression was assessed by immunohistochemistry, reverse transcription-PCR (RT-PCR), Northern Blot and Western Blot. MDR1 mRNA was detected in 40% of the breast cancers tested by RT-PCR with 40 cycles of PCR amplification. When reducing the PCR amplification cycles to 28, the MDR1 gene expression signal disappeared from breast cancers of the highest expressers; however, known MDR1 positive control normal tissues, such as adrenal, kidney, and liver continued to show an expression product. Western and Northern blots failed to demonstrate the MDR1 gene product, P-glycoprotein, in these breast cancers. In contrast, physiologic levels of P-glycoprotein was clearly detected in normal adrenal, kidney, and liver by these techniques. Immunohistochemistry confirmed that breast carcinoma cells lacked P-glycoprotein expression; however, interstitial mononuclear cells, morphologically consistent with lymphocytes or macrophages did show immunostaining in some of these breast tumors. MDR1 gene expression identified by RT-PCR was not correlated either with response to paclitaxel therapy (29 patients able to be evaluated, p = 0.34, Fisher Exact Test) or overall survival (32 breast cancer patients with clinical follow-up information, p = 0.336, log rank). In conclusion, P-glycoprotein was not expressed in breast carcinoma cells at significant levels, although it was expressed in stomal lymphocytes or macrophages. These results suggest that P-glycoprotein does not play a significant role in multidrug resistance of breast cancer.
Insights
P-glycoprotein (Pgp) is not significantly expressed in breast cancer cells, suggesting it plays a minimal role in multidrug resistance (MDR). While Pgp was detected in immune cells within tumors, its absence in cancer cells challenges its role in chemotherapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- P-glycoprotein (Pgp)-associated multidrug resistance (MDR) impacts treatment efficacy of various chemotherapeutics.
- The role of MDR1 gene expression and Pgp in breast cancer chemotherapy resistance remains debated, with conflicting data.
- Investigating Pgp expression in breast tumors is crucial for understanding treatment response and developing effective therapies.
Purpose of the Study:
- To investigate the expression of the MDR1 gene and its product, P-glycoprotein, in primary and advanced breast cancers.
- To assess the correlation between P-glycoprotein expression and responsiveness to adjuvant chemotherapy.
- To determine the role of P-glycoprotein in mediating multidrug resistance in breast cancer cells.
Main Methods:
- Expression analysis using immunohistochemistry, reverse transcription-PCR (RT-PCR), Northern Blot, and Western Blot.
- Assessment of MDR1 mRNA and Pgp protein levels in breast tumor samples and normal tissues.
- Correlation analysis of MDR1 gene expression with patient response to paclitaxel therapy and overall survival.
Main Results:
- MDR1 mRNA was detected in 40% of breast cancers via RT-PCR, but signal diminished with fewer amplification cycles.
- P-glycoprotein protein was not detected in breast carcinoma cells by Western Blot or Northern Blot, but was present in normal tissues.
- Immunohistochemistry confirmed Pgp absence in cancer cells, but detected it in stromal lymphocytes/macrophages; no correlation found between MDR1 expression and treatment response or survival.
Conclusions:
- P-glycoprotein is not significantly expressed in breast carcinoma cells.
- Detected Pgp in tumor-infiltrating immune cells suggests a potential role in the tumor microenvironment, not cancer cell resistance.
- These findings indicate P-glycoprotein does not play a significant role in multidrug resistance of breast cancer.
