Tamoxifen is a selective estrogen receptor modulator (SERM) originally developed as a contraceptive or morning-after pill .
Tamoxifen failed in this indication before its antiestrogenic properties were discovered to be efficacious in the treatment of estrogen receptor (ER)—positive breast cancer . In the last few decades, tamoxifen has become one of the most frequently prescribed anticancer drugs worldwide, also used for the chemoprevention of breast cancer for women at high risk .
In 1985, Killackey et al. suggested a possible link between tamoxifen use and the development of endometrial cancer (EC) , a claim substantiated by a series of later studies , with an increased risk of EC ranging from 1.5 to 6.9-fold in tamoxifen users . In addition, the ECs in tamoxifen users often belong to less favorable subtypes and have relatively poor prognoses . While tamoxifen has an antiestrogenic effect in the breast, it can act as a weak estrogen agonist on the endometrium. Tamoxifen-associated changes include endometrial hyperplasia, atypia, and malignancy .
On the other hand, tamoxifen has been successfully used as treatment in advanced or recurrent EC . It is suggested to be the preferred second-line hormonal therapy after first-line progestin treatment, particularly in patients with endometrial tumors and a positive estrogen receptor status, achieving response rates of 10–53% . Thus, tamoxifen is a Janus-headed drug regarding EC: on the one hand, it increases the risk for the development of this disease, and it represents a remedy for certain forms of this cancer on the other.
Endogenous and exogenous estrogens are most important risk factors for type 1 ECs, as are estrogen medication, nulliparity, early menarche, late menopause, and obesity . Tamoxifen has been used for the treatment of advanced or recurrent EC since the 1980s, at that time considered to act primarily as an antiestrogen by blocking the estrogen receptor α (ERα) . In 2001, a phase II trial by the Gynecologic Oncology Group (GOG) involving 68 eligible patients with advanced or recurrent EC was performed with 40 mg of tamoxifen/day. Three complete (4%) and four (6%) partial responders were observed . However, 50% of the patients had Grade 3 tumors and at least 20% had Type 2 tumors that were not candidates for endocrine therapy due to the lack of ER . The authors concluded that tamoxifen demonstrated modest activity at best and did not warrant further investigation as a single agent in this population .
In a subsequent phase II trial, the GOG combined tamoxifen with intermittent medroxyprogesterone acetate (MPA) or megestrol acetate. The rationale was that tamoxifen induced the expression of progesterone receptors, downregulated by continuous progestin treatment, via its estrogen-agonistic activity. Overall response rates of 33% (tamoxifen plus MPA)  and 27% (tamoxifen plus megestrol acetate)  were observed. The median overall survival was 13.14 months . Estrogen receptor α measured in metastatic EC tissue prior to hormonal therapy was statistically significantly related to clinical response to daily tamoxifen and intermittent MPA .
In 2010, a systematic Cochrane review did not find evidence that hormonal therapy improved survival in patients with recurrent or primarily advanced EC . This entry, however, looked at randomized controlled trials focusing on overall survival or 5 years disease-free survival benefits and did not include phase II trials or observational studies. Furthermore, due to insufficient and heterogeneous data, the authors were not able to pool data and perform meta-analyses. In addition, the role of hormone receptor expression was not explored . A later systematic review tried to overcome the limitations of the Cochrane analysis and found an objective response rate for tamoxifen in first-line treatment of 21.4% ± 12.1% and clinical benefit rate of 57.1 ± 10.4%. In second-line treatment, an objective response rate of 20.6 ± 13% and a clinical benefit rate of 36.3 ± 16% were calculated .
For the combination of SERMs (mostly tamoxifen) plus progestins, an objective response rate of 24.2 ± 8.3% and clinical benefit rate of 32.3 ± 15.8% were observed .
For all hormonal treatments, the response rates were higher in ER+ (26.5%) and PGR+ (35.5%) disease and lower in ER- (9.2%) or PGR- (12.1%) tumors. The response rates in second-line treatment were significantly higher when a response had been achieved in first-line HT .
Another systematic review on antiestrogen treatment in endometrial cancer found response rates for tamoxifen monotherapy ranging from 10% to 53% and for combined tamoxifen/progestin treatment of 19–58% . The authors concluded that tamoxifen alone or in combination with a progestogen should be the preferred second-line hormonal treatment. The response rates were comparable to those for first-line progestogen treatment, and toxicity was low. The efficacy of tamoxifen therapy could be further improved by selecting patients with endometrioid EC and positive ER and/or PR status, preferably based on an actual biopsy .
Tamoxifen was originally considered to be an antiestrogen before its estrogen-agonistic activities on various organs, including the uterus and the breast, became evident . This led to the paradigm “tamoxifen is an estrogen antagonist in the breast and an agonist in the endometrium”. This concept was elegantly supported by experiments from the group of Jordan. They examined the effects of tamoxifen on an estrogen-dependent human breast cancer cell line and an estrogen-dependent human EC cell line xenotransplanted into athymic mice. In the same animal, tamoxifen treatment stimulated the endometrial cancers while inhibiting the breast cancer transplant . This suggested that not the host metabolism but rather tissue-specific actions of tamoxifen led to the contrasting effects of the drug . It was later shown that the recruitment of co-activators and co-repressors of the ER might determine cell type-specific cellular responses to tamoxifen .
Tamoxifen is metabolized to a variety of molecules, including intermediates that could form protein or DNA adducts and cause DNA damage . Tamoxifen is a strong liver carcinogen in rats. The analysis of tamoxifen-DNA adducts in endometrial tissues from women with breast cancer taking tamoxifen has not provided convincing results. The risk of women treated with tamoxifen developing hepatocellular cancer is minimal, and the formation of tamoxifen-DNA adducts in endometrial tissues occurred at extremely low levels and in only a few patients .
The Dutch TAMARISK group investigated whether ECs that developed after long-term (>2 years) tamoxifen treatment for breast cancer was genetically different from ECs occurring without exposure to tamoxifen. An analysis of endometrioid ECs, serous ECs, and carcinosarcomas found neither more nor different genomic aberrations between tumors that developed after prolonged tamoxifen use and those that developed in the absence of tamoxifen .
Genes typically mutated in EC include p53 (type 2 EC), PTEN (phosphatase and tensin homology), and the DNA mismatch repair family genes. In the majority of cases, patients exposed to tamoxifen had similar mutation rates as non-exposed females with EC .
The long-term treatment of estrogen-dependent breast cancer eventually results in tamoxifen resistance, even after an initial remission of the tumors . It could be shown that tamoxifen not only lost its estrogen-antagonistic activity but could even stimulate the growth of some of these tumors . Apart from the well-characterized ERα and ERβ, a third estrogen receptor has been identified in a variety of tissues, which is located in the plasma membrane and mediates certain rapid actions of estrogens. . This seven-transmembrane receptor (GPR-30) is coupled to G-protein and activates the epidermal growth factor/MAPK pathway . As it is potently activated by estrogens, it has been renamed to G-protein coupled estrogen receptor 1 (GPER1) .
Apart from estrogens, tamoxifen and fulvestrant—considered to be a pure antiestrogen—and a number of phytoestrogens and endocrine disruptors act as agonists . The expression of GPER1 is increased in breast cancers with acquired tamoxifen resistance .
Vivacqua et al. showed that tamoxifen antagonized the activation of ERα by estradiol in Ishikawa EC cells and, at the same time, stimulated the mitogenic signaling pathways through GPER1, leading to cell proliferation . When the expression of GPER1 was suppressed, tamoxifen inhibited estrogen-induced proliferation by blocking ERα . GPER1 was found to be overexpressed in endometrial cancers where ER and PR were downregulated, and in high-risk endometrial cancers with lower survival rates .
Ignatov et al.  demonstrated a significant stimulation of endometrial cancer cell lines by tamoxifen in vitro through GPER1. In vivo, they found a significant correlation between GPER1 expression and tamoxifen-induced endometrial pathology. Tsai et al.  showed that both estradiol and tamoxifen induce the cell migration of endometrial cancers with low or no nuclear ERα, through GPER1 activation.
Tamoxifen can induce EC during chronic exposure (adjuvant or preventive therapy) at a low frequency, preferably in postmenopausal women and those with typical risk factors for EC. This risk can be minimized by detecting and treating endometrial pathologies before the initiation of tamoxifen treatment . The reduction of breast cancer mortality by adjuvant tamoxifen therapy far outweighs the slightly increased risks of EC.
The molecular mechanisms for the Janus-headed activity of tamoxifen (estrogen-antagonist/estrogen-agonist) are still elusive. Tamoxifen can act as an agonist or antagonist through ERα depending on cellular differences in co-activators or co-repressors. Tamoxifen acts as an estrogen agonist through GPER-1, which is more highly expressed in breast and endometrial cancer cells that show primary or secondary resistance to tamoxifen. As tamoxifen is and will be one of the most valuable anticancer drugs due to its high efficacy, low toxicity, and availability, further research to elucidate its mode of action should be encouraged.