Short-term Prophylactic Tamoxifen Reduces the Incidence of Antiestrogen-Resistant/Estrogen Receptor–Positive/Progesterone Receptor–Negative Mammary Tumors

Abstract

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-α (NRL-TGFα 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-TGFα mice for (a) identifying candidate biomarkers of efficacious tamoxifen chemoprevention and (b) modeling the evolution of tamoxifen resistance.The treatment and prevention of breast cancer has improved significantly due to the successful use of antiestrogens, more specifically known as selective estrogen receptor modulators (SERM) or down-regulators (SERD), and aromatase inhibitors. However, these drugs have proven to be effective only in clinical cases in which primary tumors express receptors for estrogen (ER+). Because ∼70% of all clinical breast cancer cases are ER+, the use of these antiestrogens has improved overall morbidity and mortality for a substantial number of patients.Unfortunately, not all breast cancer patients with ER+ disease benefit from such estrogen signaling manipulations. Approximately 30% of metastatic breast cancers are de novo resistant (1), and a majority that are initially sensitive develop resistance with time. This resistance is more frequent in ER+ tumors containing very low (or undetectable) levels of progesterone receptor (ER+/PR−) than in tumors containing higher progesterone receptor levels (ER+/PR+; ref. 2). In addition, in some circumstances in which growth factor and/or growth factor receptor levels are pronounced, treatment with growth factor inhibitors can improve the sensitivity of breast cancers to antiestrogen therapies and therefore promote the efficacy of such treatment (3), pointing to the importance of understanding the mechanisms underlying anti...

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“…8 In fact, many existing chemotherapies are ERa antagonists. Tamoxifen 9 is well known to remain the first line therapy for estrogen receptor positive breast cancer since the 1980s, 10,11 and it has been used successfully by more than 10 million patients. 12 However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance.…”