Correspondence to: V. Craig Jordan, Ph.D., D.Sc., Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 303 E. Chicago Ave., Olson Pavilion #8258, Chicago, IL 60611 (e-mail: vcjordan{at}nwu.edu).
Tamoxifen is the endocrine therapy of choice for all stages of breast cancer (1,2). Five years of adjuvant tamoxifen improves survival if the original tumor is classified as estrogen receptor (ER) positive, but there is virtually no benefit from tamoxifen if the tumor is ER negative (2). Tamoxifen is a nonsteroidal antiestrogen (3), so, based on the simple idea that the drug would block estrogen action at the level of the tumor (4,5), it would be hard to imagine that the concept would not rapidly translate from the laboratory to the clinic. Not so. Despite the finding by Kiang and Kennedy (6) in 1977 that ER-positive advanced disease was more likely to respond than ER-negative disease, it has taken more than 20 years and dozens of randomized clinical trials to prove the worth of the ER assay to predict the response to tamoxifen (2). Looked at another way, since Jensen's discovery and prediction that only tissues and tumors that contain ER (7,8) respond to estrogen (and can be blocked by antiestrogens), it has taken a huge clinical effort to convince oncologists on both sides of the Atlantic to select only ER-positive patients for treatment.
In contrast to the consistent response to estrogen in normal target tissues (e.g., uterus and vagina), only half of the so-called ER-positive tumors respond to adjuvant tamoxifen (2). Thus, some intrinsic mechanism is already present in half of the ER-positive breast tumors that subverts tamoxifen's action. The question has been whether the resistance mechanism is intrinsic to some tamoxifen-resistant cells containing ER or whether clones of ER-negative cells grow out, despite tamoxifen treatment. Both concepts are supported by laboratory models (9-11), but the use of immunohistochemistry to study ER in tumor tissues supports a heterogeneous tumor cell model (12).
In this issue of the Journal, Brinkman et al. (13) demonstrate the results of a novel approach to the issue of intrinsic resistance to antiestrogens and then test the concept in a companion clinical study (14). Their approach is to generate resistant cells by retrovirus insertion-mediated mutagenesis. Apparently, the ER does not play a crucial role in the resistance phenotype, since the resulting resistant cell line, developed from ER-positive ZR-75-1 cells, does not express ER (15). The resistant cells were used to identify the breast cancer antiestrogen resistance 1 (BCAR1) (note: BCAR1 is not to be confused with the BRCA1 gene that is entirely different) locus. The advance now reported is the identification of a gene with homology to the rat p130Cas adapter protein (13). The function of the protein is unknown, but it is the major tyrosine-phosphorylated protein in viral oncogene-transformed rat cells. The gene confers antiestrogen resistance when fused or transfected into estrogen responsive ZR-75-1 breast cancer cells in culture. The cells are not stimulated to grow in response to the pure antiestrogen ICI 182,780 (100 nM) or the potent tamoxifen metabolite 4-hydroxytamoxifen (1 µM) but continue to grow relentlessly, despite high concentrations of these antiestrogens (13) that would normally stop cell replication.
The human BCAR1 protein can be detected in archival frozen tumor cytosols by use of the rat antibody. About one third of the breast tumors surveyed contain measurable levels, but high levels of BCAR1/p130Cas are found in tumors positive for ERs and progesterone receptors. Unfortunately, there is the paradoxical finding of low levels in poorly differentiated tumors and high levels in older patients. The latter findings are inconsistent with the observation that tamoxifen is more likely to be effective in patients with well-differentiated tumors and in older patients.
In this study, patients with high BCAR1/p130Cas had a poorer prognosis at 8 years than those with little or no BCAR1/p130Cas. The authors also showed that advanced breast cancer patients with ER-positive tumors with high levels of BCAR1/p130Cas responded less well to tamoxifen.
So, how can these data now help in deciphering a mechanism for intrinsic drug resistance to tamoxifen? Much is known about the molecular mechanism of action of antiestrogens (16), but what does the identification of BCAR1/p130Cas tell us about how the gene subverts tamoxifen action? There is much to do before another piece of the drug resistance puzzle can be put into place and, most important, before the clinical report can be used by oncologists to determine whether a patient with an ER-positive tumor has intrinsic resistance to tamoxifen.
The question must be asked, "Is BCAR1/p130Cas coexpressed with ER in breast cancer cells in real life"? The authors elegantly show that the gene can confer resistance to antiestrogens if it is transfected into ER-positive cells, but this is not real life. It is likely, however, that knowledge of the new gene will provide answers to some of the questions raised by the results of these studies (13,14). Take the case of acquired resistance to tamoxifen. MCF-7 breast cancer cells are ER positive and can be implanted into athymic mice. The tumors eventually acquire resistance to tamoxifen after long-term treatment. However, this resistance stems from the weak estrogenicity of tamoxifen (17,18). Pure antiestrogens, which have no estrogen-like properties, block tamoxifen-stimulated growth (19,20). In the clinic, the pure antiestrogen ICI 182,780 is useful in some patients to control tumor growth following the development of resistance to tamoxifen (21). In contrast, the stable transfection of the BCAR1/p130Cas renders the ER unresponsive to both 4-hydroxytamoxifen and ICI 182,780 (13). On the face of it, knowledge of BCAR1/p130Cas is of no help at all. However, not all patients respond to ICI 182,780 after tamoxifen failure, and their tumor cells may have BCAR1/p130Cas as well as ER. Then again, an aggressive ER-negative clone of cells may grow rapidly once the majority of ER-positive cells are controlled. The BCAR1/p130Cas could be nested in the ER-negative clones in a predominantly ER-positive breast tumor.
There is much work to be done to evaluate the role of BCAR1/p130Cas in normal and malignant cells. One thought would be to consider its value as a therapeutic target. However, the messenger RNA for BCAR1/p130Cas is ubiquitous in human tissues (13), so targeting would seem to present a problem. On reflection though, one could have said the same for the ER 40 years ago. There are large amounts of ER all over a woman's body but only variable amounts in breast cancers. Had there been a concern about safety and targeting 30 years ago, hundreds of thousands of breast cancer patients would have died prematurely without tamoxifen. The challenge now is to define a role for the BCAR1/p130Cas. Specifically, do cells cotranslate ER and BCAR1/p130Cas to subvert tamoxifen's action, or is gene activation an event in an adjacent cell? Immunocytochemistry of tumors and a survey of normal and breast cancer cells lines might provide further clues about intrinsic tamoxifen resistance. The goal of further study should be to refine adjuvant tamoxifen treatment by identifying patients who would not be helped by endocrine therapy.
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