In
breast cancer, in situ
estrogen production has been demonstrated to play a major role in promoting
tumor growth.
Aromatase is the
enzyme responsible for the conversion of
androgen substrates into
estrogens. This
enzyme is highly expressed in
breast cancer tissue compared with normal breast tissue. A wine extract fraction was recently isolated from red wine that exhibited a potent inhibitory action on
aromatase activity. Using UV absorbance analysis, high-performance liquid chromatography profiling, accurate mass-mass spectrometry, and nanospray tandem mass spectrometry, most of the compounds in our red wine fraction were identified as
procyanidin B dimers that were shown to be
aromatase inhibitors. These chemicals have been found in high levels in grape seeds. Inhibition kinetic analysis on the most potent
procyanidin B dimer has revealed that it competes with the binding of the
androgen substrate with a K(i) value of 6 micro M. Because mutations at Asp-309, Ser-378, and His-480 of
aromatase significantly affected the binding of the
procyanidin B dimer, these active site residues are thought to be important residues that interact with this
phytochemical. The in vivo efficacy of
procyanidin B dimers was evaluated in an
aromatase-transfected MCF-7
breast cancer xenograft model. The
procyanidin B dimers were able to reduce
androgen-dependent
tumor growth, indicating that these chemicals suppress in situ
estrogen formation. These in vitro and in vivo studies demonstrated that
procyanidin B dimers in red wine and grape seeds could be used as chemopreventive agents against
breast cancer by suppressing in situ
estrogen biosynthesis.