Association analysis of the P-glycoprotein Transporter MDR1C3435T

polymorphism with the susceptibility to Breast Cancer

The human multidrug resistance gene 1 (MDR1) encodes a plasma membrane, Pglycoprotein (Pgp), which functions as the transmembrane efflux pump for various
structurally unrelated anticancer agents and toxins. Polymorphisms in the MDR1
gene may have an impact on the expression and function of Pgp, thereby
influencing the susceptibility to various diseases, including cancer. Recently, a
silent C3435T polymorphism in exon 26 of MDR1 has been reported to be
associated with decreased expression of Pgp in TT genotype carriers and thus it
may alter the physiological protective role of Pgp and influence disease risk. PGP
expression is an important factor regulating absorption of a wide variety of
medications. It has also been associated with intrinsic and acquired cross-resistance
to a number of structurally unrelated anticancer drugs. A single nucleotide
polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T, was correlated with
PGP protein levels and substrate uptake. Individuals homozygous for the T allele
have more than four-fold lower PGP expression compared with CC individuals. As
over expression of PGP has been associated with altered drug absorption, therapyresistant malignancies, and lower concentrations of HIV-1 protease inhibitors, this
SNP may provide a useful approach to individualize therapy. Also, a number of
various types of structurally unrelated drugs are substrates for MDR1, and MDR1
and other transporters are recognized as an important class of proteins for
regulating pharmacokinetics and pharmacodynamics.
In few studies it has been reported that T allele carriers is having 1.5-fold increased
risk for development of breast cancer. To facilitate clinical application throughout
the world, we are evaluating different allelic contribution as an association analysis
with Breast cancer patient.