The nature of tamoxifen action in the control of female breast cancer.

Tamoxifen, now in use in the breast cancer clinic worldwide, was a study subject of controversy showing an estrogenic property on one occasion and an anti-estrogenic property on another occasion. The outcomes of 4 case-control studies of tamoxifen use were disclosed through 4 publications in 1998. The contents of these reports were intriguing, not only to surgeons of breast cancer clinics, but also to researchers of oncological science in general. The results of 4 research groups, being compatible with each other, were summarized in succession as follows: a) long-term use of tamoxifen reduced the occurrence of estrogen receptor (ER)-positive tumors by 69%, but no difference in the occurrence of ER(-) tumors was seen; b) the incidence of endometrial cancer was increased in the tamoxifen group; c) in women who did not have breast cancer and who had had a hysterectomy, there was no difference of breast cancer occurrence between the placebo- and tamoxifen-arms. Nevertheless, there was a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial; d) there was also no case-control difference of breast cancer occurrence between tamoxifen- and placebo-groups, when tested in a healthy population with a strong family history; e) the beneficial effect of long term use of tamoxifen in patients with early breast cancer, as assessed in terms of recurrence reduction, survival improvement and suppression of a contralateral tumor growth, was restricted to ER(+) patients; f) there was a positive correlation between the duration of tamoxifen use and the occurrence of endometrial cancer. All these observations provide strong support to the concept of the steroid criminal theory of human carcinogenesis in general. On the basis of both tamoxifen data and other information surrounding the hormonal aspect of human carcinogenesis of multiple tumors including breast cancer, we propose that the steroid generating system, as linked to the ever changing environment, plays a cardinal role as the transmitter of steroidal signals that can be taken as a "go" sign by the local oncogene-tumor suppressor gene complex of one target tissue and as a "stop" sign by that of another target tissue. The fitness of the tamoxifen data to the steroid carcinogenesis concept was discussed in the light of experimental pathology of chemical carcinogens, including the mammocarcinogen 7,12-dimethyl-benz(a)anthracene.