MDR1 gene expression in primary and advanced breast cancer

P-glycoprotein (Pgp)-associated multidrug resistance (MDR) is related to in trinsic and acquired cross resistance to anthracyclines, vinca alkaloids, a nd other antineoplastic antibiotics. Expression of MDR1 is widely considere d to play an important role in conferring resistance to adjuvant chemothera py in women with breast tumor cells in women with disseminated disease, alt hough data supporting this view is, at best, conflicting. The expression of MDR1 gene and its gene product, P-glycoprotein, was investigated in primar y and advanced breast cancers (both previously untreated and previously tre ated on specific treatment protocols) to assess the role of P-glycoprotein in determining responsiveness to adjuvant chemotherapy. Expression was asse ssed 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 MDR I gene expression signal disappeared f rom breast cancers of the highest expressers; however, known MDR1 positive control normal tissues, such as adrenal, kidney, and liver continued to sho w an expression product. Western and Northern blots failed to demonstrate t he MDR1 gene product, P-glycoprotein, in these breast cancers. In contrast, physiologic levels of P-glycoprotein was clearly detected in normal adrena l, kidney, and liver by these techniques. Immunohistochemistry confirmed th at breast carcinoma cells lacked P-glycoprotein expression; however, inters titial mononuclear cells, morphologically consistent with lymphocytes or ma crophages 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, rho = 0.34, Fisher E xact Test) or overall survival (32 breast cancer patients with clinical fol low-up information, rho = 0.336, log rank). In conclusion, P-glycoprotein w as not expressed in breast carcinoma cells at significant levels, although it was expressed in stomal lymphocytes or macrophages. These results sugges t that P-glycoprotein does not play a significant role in multidrug resista nce of breast cancer.