EDITORIAL

Is Tamoxifen the Rosetta Stone for Breast Cancer?

V. Craig Jordan

Correspondence to: V. Craig Jordan, OBE, Ph.D., D.Sc., Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, 8258 Olson, 303 E. Chicago Ave., Chicago, IL 60611 (e-mail: vcjordan{at}northwestern.edu).

During the closing stages of the 18th century, a young French general named Napoleon Bonaparte led an expedition from France to Egypt. The goals were to: 1) establish a base for an advance over land to attack British interests in India, and 2) collect scientific information and artifacts from the ancient land of Egypt. Unfortunately, the military campaign turned into a strategic disaster when Admiral Nelson sank Napoleon‘s transport fleet in the Battle of the Nile. History was to record, however, that the Egyptian venture was not a complete failure; the scientific expedition uncovered an artifact that would become the conduit to relive the story of a lost civilization.

In the ruins surrounding the French soldiers were strange drawings known as hieroglyphs. No one had any idea what the designs meant until chance intervened. French troops who were tasked to strengthen the defenses of an abandoned fort near Rosetta uncovered a large stone slab inscribed with a text in three distinct languages: Greek, which scholars could understand, an unknown script (demotic), and hieroglyphs. The scientists in the party recognized the potential importance of the artifact in deciphering hieroglyphs and, thus, carefully preserved it for future study. For years, no one could translate the artifact, now known as the Rosetta Stone; however, a young Frenchman named Jean François Champollion did eventually succeed, and the story of a powerful empire in Egypt came alive.

Tamoxifen was discovered by the late Dr. Arthur L. Walpole, who led the antifertility program at ICI Pharmaceuticals Division (U.K.) during the early 1960s (1). Although the initial goal of developing a contraceptive was a strategic disaster and, in fact, failed, the academic community worked with staff at ICI Pharmaceuticals Division throughout the 1970s to advance a secondary goal: to develop tamoxifen as a novel targeted breast cancer treatment (2,3). For the past 20 years, tamoxifen has been the endocrine treatment of choice for all stages of estrogen receptor (ER)-positive breast cancer (4). An analysis of randomized clinical trials (5) suggested that hundreds of thousands of women are alive today because of the widespread use of adjuvant tamoxifen therapy. However, it is also clear that tamoxifen is not effective in all ER-positive breast cancers, and the question to be asked is, why? The fact that the pharmacology of tamoxifen has been rigorously investigated means that tamoxifen can now be used as a conduit to decipher the mystery of drug resistance.

In this issue of the Journal, Osborne et al. (6) describe an interaction between breast tumors that are HER-2/neu-positive and high levels of the ER coactivator SRC-3 (also called AIB1) that correlate with poor outcome when adjuvant tamoxifen is used in ER-positive disease. Although the proportion of women affected by poor outcome was only 10% of the Osborne et al. study population, the authors stress that prospective studies and further analysis of existing clinical trials are required to validate these important findings. A good place to start this analysis would be to look at the Arimidex and Tamoxifen Alone or in Combination (ATAC) adjuvant trial (7), which has already noted an early increase in disease-free survival (DFS) of breast cancer patients treated with the aromatase inhibitor anastrozole when compared with that of patients treated with tamoxifen. It is important to find out whether tumors with high SRC-3 and HER-2/neu expression that do not respond to tamoxifen might respond to an aromatase inhibitor. Then, as the authors suggest, a test would be in place to allow physicians to continue to prescribe tamoxifen for the majority of breast cancer patients.

Although it is a reasonable goal to develop a predictive test for tamoxifen resistance, it may be more useful to examine the extensive literature on the molecular pharmacology of tamoxifen and to use that information to decipher the individual associations in clinical studies. In this way, the predictable changes that tamoxifen can induce in the breast cancer cell could provide a rational road map for patient care.

Although Osborne et al. (6) focus on two apparently independent variables, HER-2/neu expression and the ER coactivator SRC-3, it is, in fact, the amount of ER that links the previous two factors together, and all three of these factors must be used to decipher the consequences of antihormone action. This triumvirate (i.e., group of three controlling variables) appears to regulate the intrinsic or rapidly acquired resistance observed with tamoxifen therapy (6). In other words, tamoxifen‘s action as an antiestrogen is subverted by the molecular configuration of the cell, or the cell has adaptive mechanisms that rapidly convert tamoxifen from an antiestrogen to an estrogen. Indeed, knowledge of the triumvirate of ER, cell-surface signaling, and coactivators (Fig. 1Go) has been used previously to understand the actions of selective estrogen receptor modulators (SERMs) (e.g., tamoxifen and raloxifene). Simply stated, SERMs are antiestrogens at some target tissue sites such as the breast but estrogens at others such as bone. Shang and Brown (8) have recently shown that the concentration of another ER coactivator SRC-1, which is related to SRC-3, but not SRC-3 itself, can enhance some ER-mediated genes in endometrial cancer cells where tamoxifen has estrogen-like effects. Levels of SRC-1 were transiently increased or decreased in cells to modulate gene activation by tamoxifen. However, this process did not work for wild-type breast cancer cells. Unfortunately, Shang and Brown (8) did not include the critical role of active cell-surface signaling in their experimental model, despite the fact that Brown‘s group has already shown that cell-surface signaling can enhance SRC-3 phosphorylation and ER activation (9).



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Fig. 1. Integrated mechanism for the target site-specific action of selective estrogen receptor modulators (SERMs) in breast and uterine cancer. Two extremes of antiestrogenic or full estrogenic actions are shown. Estrogen-like actions could occur in cells expressing an excess of coactivators (CoAs) and/or a decrease in corepressors (CoRs). The charged surface of a tamoxifen–estrogen receptor (ER) complex at AF2b prevents CoR binding. The estrogenic action would be amplified by surface signaling with dimers of epidermal growth factor receptor (EGFR) and HER-2/neu activating tyrosine kinases (tks). The phosphorylation cascade can activate either AF-1 on ER-alpha (ER{alpha}) directly or the excess of CoAs in a high-ER environment. Reduced levels of ER prevent the signal transduction pathway and promote antiestrogenic actions in a surface-silent cell. Reprinted from Cancer Cell, 1, Jordan VC, The secrets of selective estrogen receptor modulation: cell specific coregulation, 215–217, 2001, with permission from Elsevier Science.

 
The triumvirate of ER, HER-2/neu expression, and coactivators, clearly needs to be coordinated to work in harmony, and it would be valuable to learn whether there is an innate mechanism that accelerates resistance to tamoxifen. Arguably, the most important component of this resistance is the ER itself. Moreover, ER levels may be critical for SERM resistance. Unfortunately, Osborne et al. (6) do not report the quantitation of ER levels, despite the fact that they use ligand-binding assays to classify individual tumors precisely. Antiestrogen binding to the ER increases the transcription of the HER-2/neu gene by releasing ER coactivators (e.g., SRC-1) from the estradiol–ER complex. These coactivators then activate the HER-2/neu promoter (10). This cancer-cell survival system facilitates cell-surface signaling and ultimately subverts tamoxifen‘s action through the phosphorylation of coactivators (9) and ER. Importantly, tamoxifen–ER complexes have a built-in mechanism to enhance their own long-term survival so that the complexes can become promiscuous at gene target sites within the cell (Fig. 1Go). As one might imagine, the ER is a powerful intracellular messenger that needs to be destroyed rapidly to prevent a continuing response. This process is successfully achieved through ubiquitinization of the estradiol–ER complex and destruction of the ER by the proteosome. However, the tamoxifen–ER complex tends to still accumulate because of poor ubiquitinization (11). The destruction process is controlled through a region around D538 that is exposed to and apparently impaired on the surface of the tamoxifen–ER complex (12).

The questions that then arise are, if ER and cell-surface signaling are increased with tamoxifen, then what is the role of coactivators, and what regulates them? Osborne et al. (6) state that Riegel‘s group (13) found that the coactivator SRC-3 is a rate-limiting factor for estrogen-dependent growth of MCF-7 breast cancer cells in culture. Nevertheless, estrogen causes a reduction in SRC-3 mRNA, but antiestrogens cause an increase in SRC-3 mRNA levels (14). Thus, it is as though the cancer cell is trying to enhance signal transduction through the now impaired tamoxifen–ER complex. In addition, there is an exon deletion variant of SRC-3 that has been reported to be extremely potent at activating steroid hormone receptors and epidermal growth factor receptor (EGFR) signal transduction (15). This variant, therefore, may also have increased mRNA levels in response to antiestrogens. Be that as it may, the increase in SRC-3 by antiestrogens requires protein synthesis—that is, the increase occurs indirectly through a secondary signaling mechanism shown to be transforming growth factor beta (TGF-{beta}) (14). It should, therefore, come as no surprise to discover that tamoxifen increases levels of TGF-{beta} in both breast cancer cells themselves (16) and in stromal cells (17). Clearly, this mechanism—to enhance the production of coactivators and their variants—should also be anticipated to increase the signal transduction of the accumulating tamoxifen–ER complex in the correct cellular context, i.e., a cancer cell with high HER-2/neu expression levels (Fig. 1Go).

The activation of the tamoxifen–ER complex, either directly (through phosphorylation cascades) or indirectly (through phosphorylation of the coactivator), is an elegant solution to the problem of tamoxifen-resistant disease. Nevertheless, the question must be asked whether the physician can already subvert the power of the triumvirate by the judicious use of new approaches to endocrine therapy in select patients? In laboratory models of acquired drug resistance to tamoxifen, the antiestrogen fulvestrant (ICI 182,780) controls tumor growth by destroying the ER (18,19). Fulvestrant is effective in approximately one in five patients who are resistant to tamoxifen (20,21). Furthermore, the improved DFS observed with anastrozole (7) most likely also results from the disruption of the triumvirate (Fig. 1Go). The inhibition of estrogen synthesis by an aromatase inhibitor will prevent the formation of an ER complex at the target gene sites of tumor cell survival. It is reasonable to say that, for the clinician, the new generation of endocrine agents will enhance therapeutic benefits without further detailed knowledge of individual mechanisms. The challenge will be, therefore, to address the treatment of antihormonal therapy-resistant ER-positive patients. It is possible, however, that the ER will again be the target of the fall of the triumvirate (22).

In conclusion, Dr. Bernard Fisher recently presented a lecture entitled "Tamoxifen: the Rosetta Stone or Hope Diamond?" There is no doubt that the merits of tamoxifen have been vigorously contested and debated (23–25). Nevertheless, the combined advantages of being a pioneering life-saving medicine (5,26) and an agent to decipher the molecular perturbations of the breast cancer cell make tamoxifen, on balance, the Rosetta Stone.

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18 Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, et al. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 1995;87:746–50.[Abstract]

19 Lee ES, MacGregor Schafer J, Yao K, England G, O‘Regan RM, de los Reyes A, et al. Cross resistance of triphenylethylene-type antiestrogen but not ICI 182,780 in tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 2000;6:4893–9.[Abstract/Free Full Text]

20 Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396–403.[Abstract/Free Full Text]

21 Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 2002;20:3386–95.[Abstract/Free Full Text]

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