Endocr Relat Cancer. 1999 Jun;6(2):235-43.  

The potential of aromatase inhibitors in breast cancer prevention.

Santen RJ, Yue W, Naftolin F, Mor G, Berstein L.

Department of Medicine, University of Virginia, Charlottesville 22908, USA.

Substantial evidence supports the concept that estrogens cause breast cancer in
animals and in women but the precise mechanism is unknown. The most commonly
held theory is that estrogens stimulate proliferation of breast cells and thus
statistically increase the chances for genetic mutations which could result in
cancer. Another theory is that estrogen metabolism generates oxygen-free
radicals and quinones which produce both stable and unstable DNA adducts. Both
result in genetic mutations which accumulate and could ultimately cause cancer.
A major criticism of the latter hypothesis is that breast tissue contains
insufficient concentrations of estrogen for accumulation of genotoxic
metabolites. Our hypothesis is that breast tissue estrogen levels, as a result
of in situ synthesis, are much higher than previously thought. We and others
have shown that estrogen can be made in the breast itself through conversion of
androgens to estrogens, a process catalyzed by the enzyme aromatase. The levels
of estrogen in the breast increase when aromatase is overexpressed. With
sufficient amounts of aromatase in breast tissue, enough estradiol as substrate
should be available to allow formation of substantial amounts of genotoxic
metabolites. We postulate that aromatase overexpression may in this way cause
breast cancer. As evidence supporting this concept, four animal models of
aromatase overexpression and either breast cancer or premalignant lesions have
been described. We have provided evidence that normal breast tissue can make
estrogen and that certain stimulatory compounds can increase aromatase activity
in the breast by nearly 10,000-fold. If our concepts are correct, it might be
possible to prevent breast cancer by blocking the aromatase enzyme. Drugs are
currently available to inhibit aromatase nearly completely without causing
significant side-effects. Aromatase inhibitors might be more effective than
antiestrogens in preventing breast cancer because of their dual role to block
both initiation and promotion of breast cancer. To inhibit the initiation
process, these inhibitors would reduce levels of the genotoxic metabolites of
estradiol by lowering estradiol concentrations in tissue. At the same time,
aromatase inhibitors would inhibit the process of tumor promotion by lowering
tissue levels of estradiol and thus blocking cell proliferation. These concepts
provide a strong rationale for studies of aromatase inhibitors to prevent breast
cancer.

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