Editorial: Estrogen Receptor Mutations in Breast Cancer—An Anticipated “Rediscovery?”

The history of science is filled with stories describing rediscovery of previous knowledge. Perhaps the most famous is the law of genetics originally postulated in 1866 by Mendel and “rediscovered” by Hugo de Vries and Carl Correns early in the 20th century. Mendel had published his work in a relatively obscure scientific journal and, given the challenges facing the propagation of knowledge in that era, it is not difficult to envisage why his discovery received little attention by the scientific community at the time. This phenomenon is less and less likely to occur as current information technology, now fully embraced by this journal through rapid online-only publication, allows access, almost instantaneously, to the latest scientific findings as well as to past publications deposited in electronic archives. Today's “rediscoveries” are more likely to be driven by studying the same biological and/or medical problem but with better and more advanced technologies.

“If history repeats itself, and the unexpected always happens, how incapable must Man be of learning from experience”– George Bernard Shaw, 1925 Nobel Prize for Literature

The growth and proliferation of hormone-dependent cancers, such as most those originating from the prostate in men and the breast in women, are driven by the presence of nuclear receptors that transduce the action of estrogens and androgens in those tissues. Indeed, inhibition of androgen receptor and estrogen receptor (ERα) action by directly antagonizing the receptors with drugs such as flutamide and tamoxifen, or by decreasing levels of circulating hormones via surgical procedures or inhibition of steroidogenesis, has proven to be a remarkably successful strategy with which to treat these cancers. However, resistance often emerges after prolonged exposure to these drugs or hormone withdrawal; thus, understanding the molecular mechanisms underlying how cancer cells acquire resistance to these treatments has been an intense field of research. Naturally, the receptors themselves have been the focus of most of these investigations. In prostate cancer, it has been known for some time that androgen receptor mutations are extremely rare in the early untreated stage of the disease, but are quite common (10–30%) in castration-resistant prostate cancers. Surprisingly, given the importance of ERα in the etiology of breast cancer, mutations in the coding region of ESR1, the gene encoding ERα, had not been established to date as being a mechanism of resistance during the progression of the disease.

Recent technological advances in high-throughput sequencing have allowed researchers to begin mapping the mutational landscape contributing to the oncogenic process in tissues of different origins. In the breast, sequencing of a large number of primary ERα-positive tumors identified mutations in nearly all genes previously implicated in the disease, as well as several novel gene mutations (1). However, this study did not identify mutation in the coding region of ESR1, indicating that, as observed in prostate cancer, mutation in the receptor does not contribute to the initiation of this hormone-dependent cancer. Yet, the search for ERα mutations in breast cancer tumors continued at a vigorous pace. Recently, two studies reported activating somatic ESR1 mutations in metastatic breast tumors, some of which were obtained from patients who had received aromatase inhibitors (2, 3). Remarkably, most recurrent mutations alter a group of amino acids located within a domain referred to as activation function 2, predominantly at tyrosine 537. The activation function 2 region is responsible for making contact with coactivator proteins upon ligand binding by the receptor, and mutations in these residues result in constitutive activation of the receptor. These mutations generate receptors that are active in the absence of estrogens and thus could play a role in acquired resistance to aromatase inhibitors. On the other hand, this work showed that these mutant receptors still bind and respond to tamoxifen and are thus unlikely to develop in the context of antiestrogen treatment.

These two important studies, which used new technologies that included comprehensive clinical sequencing programs, led to a better understanding of the mechanisms of therapeutic resistance to antiestrogens and aromatase inhibitors. However, could these discoveries have been anticipated and the main conclusion already known? More than 15 years ago the group of Dr. Fuqua's and associates (4) had identified the same ERα mutation in a metastatic breast cancer, and a follow-up study (5) demonstrated that this constitutively active mutant receptor maintains its response to tamoxifen and fulvestrant. Taken together, these prior studies suggested that this particular type of modified receptors was unlikely to contribute to resistance toward antiestrogens in breast cancer therapy and that more potent antiestrogens could be of use to treat patients with this type of mutation. Thus, although the latest work used “highly innovative” state-of-the-art technology, in fact, these “newly” discovered ERα mutations and their impact on ERα function and response to antiestrogens were described many years ago using what would now be considered “standard” approaches.

Scientists should never forget that their current work, no matter how innovative, original, and technologically advanced, is always built on the previous labor of others. Judicious and fair use of citations of previous publications is an essential part of writing a scientific paper. Acknowledging prior findings will never diminish a great new study, even when a portion of the work and its conclusion could appear to some as a “rediscovery.”

Vincent Giguère, PhD, FRSC
Editor, Molecular Endocrinology