Targeting antihormone resistance in breast cancer: a simple solution.

During the past 30 years a dramatic change has occurred in the approach to the treatment of breast cancer. Thirty years ago, nonspecific combination cytotoxic chemotherapy was going to cure breast cancer, advanced breast cancer was the only stage being treated with drugs and the estrogen receptor (ER) was considered a potential predictive test for identifying the one in three women who would respond to endocrine ablative surgery. These changes occurred as a result of two principal factors: ER evolved from being viewed as a predictive marker of endocrine responsiveness to becoming a molecular target for tumor selective drugs [1]; and tamoxifen, a potential antifertility agent that failed in the clinic [2], was re-invented as a breast cancer drug targeted to the ER, which was used, pre-emptively, to destroy micrometastases with long-term adjuvant therapy following surgery [3]. The result today is that 400000 women who would have died prematurely from breast cancer are alive; and the pioneering medicine, tamoxifen, has opened the door to new advances in endocrine therapeutics and chemoprevention [3]. However, there is also new knowledge resulting from a shift from a treatment approach that employed a combination of nonspecific cytotoxic chemotherapies, to an approach that relies on a single agent targeted approach with tamoxifen: an understanding of drug resistance. There are two clearly defined categories of resistance to tamoxifen. First, acquired resistance occurs after many years of successful treatment in select ER-positive breast cancer patients. Secondly, intrinsic resistance is evidenced by no initial response of the tumor to antiestrogen treatment. Intrinsic resistance obviously occurs in the ER-negative patient, but ER-positive patients who are refractory to antiestrogen therapy remain a challenge for the physician. Clearly, a laboratory test to identify ER-positive patients who are unresponsive to antiestrogens would be an advantage. Perhaps of even greater use would be a method to convert the ER-positive hormone, nonresponsive, patient to a responsive patient. This would be an enormous advance and would, perhaps, double our current response rates in breast cancer. In this issue of Annals of Oncology, deGraffenried et al. [4] illustrate a simple strategy for restoring antiestrogen responsiveness in cells engineered to be intrinsically resistant. Although it must be stressed that these are preliminary studies in vitro, there are some interesting principles that could be integrated into future research protocols [4]. During the last decade it has become increasingly clear that breast cancer cell survival depends on enhanced cell-surface signaling mechanisms that override apoptotic mechanisms. The trick in targeted cancer therapy is to impair cell survival selectively, but enhance apoptosis. Although much work is being done to inactivate the MAP kinase pathway, through the blockade of EGFR tyrosine kinases or the use of antibodies to HER2/neu [5], deGraffenried and coworkers are building on the work of Campbell et al. [6], who have demonstrated that phosphatidylinositol (PI) 3-kinase and AKT activate the ER in the absence of estrogen. Increased phosphorylation of the ER–tamoxifen complex occurs, which completely protects breast cancer cells from tamoxifen-induced apoptosis. Indeed, inducible AKT activity can dominate the survival pathway for the breast cancer cell and promote resistance to chemotherapy, trastuzumab (Herceptin) and tamoxifen [7]. deGraffenried and coworkers [4] developed a constituitively active AKT-transfected breast cancer cell line to demonstrate that tamoxifen is inactive and does not control growth. Rather than using traditional blockers of the PI3 kinase AKT pathway, deGraffenried et al. [4] examined the ability of eicosapentaenoic acid (EPA), an essential ω-3 fatty acid, and found that tamoxifen sensitivity is restored. The essential ω-6 fatty acid, linoleic acid, is used as an ineffective comparator. It is clear, however, from the data presented that the mechanism is not simply a blockade of the ectopic AKT, but there is sufficient tantalizing evidence in the literature to suggest that ω-3 fatty acids do inhibit protein kinases [8] and that they can increase the sensitivity of cancer cells to chemotherapy by enhancing apoptosis [9, 10]. The PI3 kinase AKT target is also proving to have important therapeutic value. A recent report [11] has focused attention on deguelin, a natural product that causes apoptosis in premalignant human bronchial epithelial cells by blocking phosphorylation of AKT. Since premalignant lung cancer cells have higher levels of phosphorylated AKT than normal lung epithelial cells, this opens the door to chemoprevention and therapy in lung cancer. There is no reason to believe that the AKT target should not now be viewed as one of the multiple survival pathways that must be destroyed to first control and then, hopefully, cure cancer. The goal for the future will be not only to enhance our understanding of the multiple mechanisms of cancer cell survival, but also to integrate into our thinking the huge literature that has accumulated for decades on the benefits of fish oil diets, i.e. a prime source of ω-3 fatty acids. Clues regarding steps that can be taken to mount a logical assault on the early stages of carcinogenesis (prevention) or on the established tumor (treatment) are slowly emerging. Currently, there are incredible opportunities for a new generation of translational scientists to build on existing knowledge about diet, cancer and molecular biology so that response rates in treatment will be enhanced in the future. This will be possible not only through the heroic effort by the pharmaceutical industry to screen millions of compounds, but also, as illustrated