Although many
estrogen receptor-positive (ER+) breast
cancers are effectively treated with
selective estrogen receptor modulators and down-regulators (
SERM/SERD), some are highly resistant. Resistance is more likely if primary
cancers are devoid of
progesterone receptors (PR-) or have high levels of
growth factor activity. In this study, a transgenic mouse line that expresses
transforming growth factor-alpha (NRL-
TGFalpha mice) and that develops ER+/PR- mammary
tumors was used to assess the possible effects of (a) therapeutic delivery of the
SERM,
tamoxifen, or SERD, ICI I82,780 (ICI), on the growth of established
tumors and (b) short-term prophylactic
tamoxifen administration on the initial development of new mammary
tumors. To determine the
therapeutic effects of
tamoxifen and ICI on the growth of established
tumors, mice were exposed to 3 weeks of drug treatment. Neither drug influenced
tumor growth or glandular pathology. To determine if early prophylactic
tamoxifen could alter
tumorigenesis, a 60-day
tamoxifen treatment was initiated in 8-week-old mice. Compared with placebo-treated mice,
tamoxifen reduced
tumor incidence by 50% and significantly decreased the degree of mammary
hyperplasia. Prophylactic
tamoxifen also significantly extended the life span of
tumor-free mice. These data show that in this mouse model, established ER+/PR- mammary
tumors are resistant to
SERM/SERD treatment but the development of new mammary
tumors can be prevented by an early course of
tamoxifen. This study validates the utility of NRL-
TGFalpha mice for (a) identifying candidate
biomarkers of efficacious
tamoxifen chemoprevention and (b) modeling the evolution of
tamoxifen resistance.