Sensitivity and insensitivity of breast cancer to tamoxifen

Tamoxifen is the endocrine treatment of choice for breast cancer. In several laboratory models in vivo tamoxifen is a tumoristatic agent. When MCF-7 breast cancer cells are inoculated into athymic mice, palpable tumors do not grow unless the animals are treated with estrogen, and tamoxifen inhibits estrogen-stimulated growth. If tamoxifen is stopped, tumors regrow. These results suggest that adjuvant tamoxifen therapy should involve long treatment periods (even lifetime) to prevent tumor recurrence. Unfortunately resistance to therapy and patient relapse inevitably occur, and such disease recurrence involving tamoxifen resistance is difficult to treat successfully. A laboratory model of endocrine therapy failure has been developed. When athymic mice with MCF-7 tumors are treated for 6–8 months with tamoxifen, several tumors grew and continued to grow in tamoxifen-treated mice. These estrogen receptor-positive tumors grow with either tamoxifen or estradiol. Tamoxifen-stimulated tumor growth has been observed in human endometrial tumors implanted into athymic animals. Growth of these tamoxifen-stimulated tumors can be inhibited with the pure antiestrogen ICI 164,384 upon withdrawal of tamoxifen. These data are discussed in terms of treatment strategies for tamoxifen-failed patients.     

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.     

Selective estrogen receptor modulators (SERMs) in the practice

Selective estrogen receptor modulators (SERMs) represent a growing class of compounds that act as either estrogen receptor gonists or ntagonists in tissue-selective manner. SERMs with the appropriate selectivity profile offer the opportunity to dissociate the favorable bone and cardio-vascular effects of estrogen from its unfavorable stimulatory effects on the breast and uterus. The triphenylethylene drug tamoxifen proved to be invaluable to treat and protect against breast cancer and bone loss, probably reduces cardiovascular risk, but had side effects on uterus similar to natural estrogens. The tamoxifen derivate toremifene is also used to treat breast cancer, but has less effect on bone. The non-steroidal benzothiophene derivate, raloxifene, is the best SERM available thus far. It has the potential to prevent breast cancer (like tamoxifen), but has better profile in its actions on bone and cardiovascular system (produces a rapid reduction of serum cholesterol, decreases fibrinogen and lipoprotein, improves the vascular epithelial function, attenuates vascular intimal thickening, etc.). It does not increase the incidence of endometrial cancer. Compounds of this class are the first step in developing the perfect hormone replacement and other multitargeted therapy. This review summarizes the recent important knowledge about SERMs.     

Targeted anti-estrogens to treat and prevent diseases in women

The estrogen receptor has been successfully targeted with the anti-estrogen tamoxifen to treat all stages of breast cancer. Because tamoxifen is a partial agonist, it exhibits target-site specificity: it acts as an anti-estrogen in the breast to inhibit tumor growth, while exhibiting estrogenic effects on bones and lipid metabolism. Therefore, tamoxifen has the added benefit of maintaining bone density and reducing the risk of myocardial infarction in postmenopausal women.However, undesirable side effects of tamoxifen preclude its use as a hormone replacement therapy for otherwise healthy women. New anti-estrogens are currently being developed that may prevent osteoporosis, breast and endometrial cancer, and reduce the risk of myocardial infarction.     

The evolution of nonsteroidal antiestrogens to become selective estrogen receptor modulators

The discovery of the first nonsteroidal antiestrogen ethamoxytriphetol (MER25) in 1958, opened the door to a wide range of clinical applications. However, the finding that ethamoxytriphetol was a “morning after” pill in laboratory animals, energized the pharmaceutical industry to discover more potent derivatives. In the wake of the enormous impact of the introduction of the oral contraceptive worldwide, contraceptive research was a central focus in the early 1960’s. Numerous compounds were discovered e.g., clomiphene, nafoxidine, and tamoxifen, but the fact that clinical studies showed no contraceptive actions, but, in fact, induced ovulation, dampened enthusiasm for clinical development. Only clomiphene moved forward to pioneer an application to induce ovulation in subfertile women. The fact that all the compounds were antiestrogenic made an application in patients to treat estrogen responsive breast cancer, an obvious choice. However, toxicities and poor projected commercial returns severely retarded clinical development for two decades. In the 1970’s a paradigm shift in the laboratory to advocate long term adjuvant tamoxifen treatment for early (non-metastatic) breast cancer changed medical care and dramatically increased survivorship. Tamoxifen pioneered that paradigm shift but it became the medicine of choice in a second paradigm shift for preventing breast cancer during the 1980’s and 1990’s. This was not surprising as it was the only medicine available and there was laboratory and clinical evidence for the eventual success of this application. Tamoxifen is the first medicine to be approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at high risk. But it was the re-evaluation of the toxicology of tamoxifen in the 1980’s and the finding that there was both carcinogenic potential and a significant, but small, risk of endometrial cancer in postmenopausal women that led to a third paradigm shift to identify applications for selective estrogen receptor (ER) modulation. This idea was to establish a new group of medicines now called selective ER modulators (SERMs). Today there are 5 SERMs FDA approved (one other in Europe) for applications ranging from the reduction of breast cancer risk and osteoporosis to the reduction of menopausal hot flashes and improvements in dyspareunia and vaginal lubrication. This article charts the origins of the current path for progress in women’s health with SERMs.     

The development, application and limitations of breast cancer cell lines to study tamoxifen and aromatase inhibitor resistance

Estrogen plays important roles in hormone receptor-positive breast cancer. Endocrine therapies, such as the antiestrogen tamoxifen, antagonize the binding of estrogen to estrogen receptor (ER), whereas aromatase inhibitors (AIs) directly inhibit the production of estrogen. Understanding the mechanisms of endocrine resistance and the ways in which we may better treat these types of resistance has been aided by the development of cellular models for resistant breast cancers. In this review, we will discuss what is known thus far regarding both de novo and acquired resistance to tamoxifen or AIs. Our laboratory has generated a collection of AI- and tamoxifen-resistant cell lines in order to comprehensively study the individual types of resistance mechanisms. Through the use of microarray analysis, we have determined that our cell lines resistant to a particular AI (anastrozole, letrozole, or exemestane) or tamoxifen are distinct from each other, indicating that these mechanisms can be quite complex. Furthermore, we will describe two novel de novo AI-resistant cell lines that were generated from our laboratory. Initial characterization of these cells reveals that they are distinct from our acquired AI-resistant cell models. In addition, we will review potential therapies which may be useful for overcoming resistant breast cancers through studies using endocrine resistant cell lines. Finally, we will discuss the benefits and shortcomings of cell models. Together, the information presented in this review will provide us a better understanding of acquired and de novo resistance to tamoxifen and AI therapies, the use of appropriate cell models to better study these types of breast cancer, which are valuable for identifying novel treatments and strategies for overcoming both tamoxifen and AI-resistant breast cancers.     

Signaling by estrogens and tamoxifen in the human endometrium

Tamoxifen is used as adjuvant treatment for postmenopausal breast cancer patients. The mechanism of action of tamoxifen in breast cancer patients is that tamoxifen inhibits growth of cancer cells by competitive antagonism for estrogens at the estrogen receptor (ER). In the endometrium, tamoxifen has an effect that varies with the ambient concentration of estrogen: in premenopausal women (high estrogen levels), tamoxifen displays an estrogen-antagonistic effect, while in postmenopausal women (low estrogen levels), tamoxifen displays an estrogen-agonistic mode of action. Here, using microarray technology we have compared estrogen signaling with tamoxifen signaling in the human endometrium. It was observed that on the one hand tamoxifen-treatment results in modulation of expression of specific genes (370 genes) and on the other hand tamoxifen-treatment results in modulation of a set of genes which are also regulated by estrogen treatment (142 genes). Upon focusing on regulation of proliferation, we found that tamoxifen-induced endometrial proliferation is largely accomplished by using the same set of genes as are regulated by estradiol. So, as far as regulation of proliferation goes, tamoxifen seems to act as estrogen agonist. Furthermore, tamoxifen-specific gene regulation may explain why tamoxifen-induced endometrial tumors behave more aggressively than sporadic endometrial tumors.     

Genotoxicity of the some selective estrogen receptor modulators: a review

The objective of this article is to review genotoxicological profile of the major selective estrogen receptor modulators, including clomiphene, tamoxifen, toremifene, raloxifene. These drugs have been used for infertility treatment and breast cancer prevention in high risk-women. However, some studies reported that especially tamoxifen is a genotoxic agent and is related with endometrial cancer. Our review indicate that clomiphene and tamoxifen were found as genotoxic agent in majority of the tests. However published reports showed that toremifene is a weakly genotoxic agent. The genotoxic effects of raloxifene are still poorly known. Further genotoxicity studies should be conducted especially for raloxifene.     

Cytotoxicity of tamoxifen in normal and tumoral cell lines and its ability to induce cellular transformation in vitro

Tamoxifen (TAM) is a non-steroidal anti-estrogen used to treat patients with estrogen receptor-positive breast cancer and as a chemopreventive agent against breast cancer in high risk pre- and post-menopausal women. However, recent studies have shown that tamoxifen causes endometrial and hepatic cancer. In this study, we examined the effects of tamoxifen (5, 10, 25 and 50 microM) on the growth and proliferation of nine tumoral cell lines (UACC62, MCF-7, NCI-460, K-562, OVCAR-03, PC-03, HT-29, 786-0, NCI-ADR) and non-tumoral cell lines (3T3, V79, MDCK, VERO). Chinese hamster lung fibroblasts (V79) were the most sensitive lineage to tamoxifen, with 21.6% of the cells showing apoptosis at 50 microM TAM. Microscopic analysis showed that, the cellular transformation caused by TAM in V79 cells was similar to that seen with 7,12-dimethylbenz(a)anthracene, thus indicating the carcinogenicity of TAM.     

The consequences of exhaustive antiestrogen therapy in breast cancer: estrogen-induced tumor cell death

Forty years ago, the endocrine treatment for breast cancer was a last resort at palliation before the disease overwhelmed the patient (1). Ovarian ablation was the treatment of choice for the premenopausal patient, whereas either adrenalectomy or, paradoxically, high-dose synthetic estrogen therapy were used for treatment in postmenopausal patients. A reduction or an excess of estrogen provoked objective responses in one out of three women. Unfortunately, there was no way of predicting who would respond to endocrine ablation, and because so few patients responded there was no enthusiasm for developing new endocrine agents. All hopes for a cure for breast cancer turned to appropriate combinations of cytotoxic chemotherapy. Today tamoxifen, a nonsteroidal antiestrogen (2), has proven to be effective in all stages of premenopausal and postmenopausal breast cancer, and several new endocrine strategies, including aromatase inhibitors, luteinizing-hormone releasing hormone (LHRH) superagonists, and a pure antiestrogen (fulvestrant), are now available for breast cancer treatment. Additionally, tamoxifen and raloxifene, a related compound, are used to reduce the risk of breast cancer and osteoporosis, respectively, in high-risk groups (3). Hormonal modulation and strategies to prevent the actions of estrogen in the breast are ubiquitous. However, with successful changes in treatment strategies comes the consequence of change. This minireview will describe the current strategies for the treatment and prevention of breast cancer and present emerging new concepts about the consequences of exhaustive antiestrogen treatment on therapeutic resistance.     

Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice

Ospemifene is a new selective estrogen receptor modulator (SERM) that is being developed for the treatment of urogenital atrophy and osteoporosis. Similarly to other SERMs, ospemifene exhibits antiestrogenic effects in breast tissue, which led to the hypothesis that it may be a potential breast cancer chemopreventive agent. We first assessed the ability of ospemifene, compared to tamoxifen and raloxifene, to prevent dimethylbenzanthracene (DMBA)-induced mammary tumors in female Sencar mice. Ospemifene (N = 18), tamoxifen (N = 20) and raloxifene (N = 17), each dosed at 50 mg/kg, were administered daily by oral gavage, in combination with 20 microg DMBA for the first 6 weeks. Control mice (N = 21) received vehicle plus DMBA only for the first 6 weeks. Daily treatment then continued for 37 weeks. As hypothesized, ospemifene greatly reduced the incidence of mammary carcinomas compared to control mice (p = 0.003), similar to tamoxifen (p = 0.0004); however, in the raloxifene group, no significant effect was seen in mammary tumor prevention (p = 0.20). A follow-up study comparing ospemifene (N = 20) to tamoxifen (N = 20) in the same model was then performed to confirm the results of the first study. The results of the follow-up study, which extended the treatment to 52 weeks, confirmed the results of our previous study, with ospemifene (p = 0.01) and tamoxifen (p = 0.004) significantly decreasing mammary carcinomas compared to controls. The results of these two studies suggest that women taking ospemifene for osteoporosis and/or urogenital atrophy may further benefit from ospemifene's breast cancer chemopreventive effects.     

Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations

Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E₂ or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.     

Inhibition of aromatase: insights from recent studies

Aromatase is the rate limiting enzyme that catalyzes the conversion of androgens to estrogens. Blockade of this step allows treatment of diseases that are dependent upon estrogen. Over the past two decades, highly potent and specific aromatase inhibitors have been developed which block total body aromatization by over 99%. An important recent question is whether aromatase inhibitors are superior to the antiestrogens for treatment of hormone-dependent breast cancer. The third generation aromatase inhibitors have been compared to tamoxifen for the treatment of breast cancer in the advanced, adjuvant, and neoadjuvant settings. All of these studies suggest the superiority of aromatase inhibitors over tamoxifen. The mechanism responsible for the superiority of the aromatase inhibitors relates to the estrogen agonistic effects of tamoxifen. During exposure to estrogen deprived conditions and to tamoxifen, breast cancer cells adapt and upregulate the MAP kinase and PI-3 kinase pathways. These growth factor signaling pathways potentiate the estrogen agonistic properties of tamoxifen. Data from a large adjuvant therapy trial (ATAC trial) provide evidence that the aromatase inhibitors may also be superior for breast cancer prevention. The mechanism for superiority in this setting probably relates to the genotoxic effects of estradiol metabolites. The aromatase inhibitors may be also useful for the treatment of endometriosis and for ovulation induction as evidenced by preliminary data. The recent advances in development of the aromatase inhibitors clearly demonstrate the utility of these agents for treatment of breast cancer and potentially for other indications.     

Progress in the prevention of breast cancer: concept to reality

In 1936, Professor Antoine Lacassagne suggested that breast cancer could be prevented by developing drugs to block estrogen action in the breast. Jensen discovered the physiologic target, the estrogen receptor, that regulates estrogen action in its target tissues and Lerner discovered the first nonsteroidal antiestrogen MER25. However, the success of tamoxifen as a treatment of breast cancer opened the door for the testing of the worth of tamoxifen to reduce breast cancer incidence in high-risk women. In 1998, Fisher showed that tamoxifen could reduce breast cancer incidence by 50%. Nevertheless, only half the women who develop breast cancer have risk factors other than age, so what can be done for women without risk factors? The recognition that nonsteroidal antiestrogens have the ability to modulate estrogen action selectively has advanced the design and development of new drug for multiple diseases. Tamoxifen and raloxifene maintain bone density and raloxifene is now used to prevent osteoporosis and is being tested as a preventive for coronary heart disease and breast cancer. The drug group is now known as selective estrogen receptor modulators (SERMs) and the challenge is to design new agents for multiple applications. If the 20th century was the era of chemotherapy, the 21st century will be the era of chemoprevention.     

Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer

Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.

ICI 182, 780 (Faslodex™), a steroidal estrogen antagonist, is the first in a new class of agent—an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity.

Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.     

Strategies for breast cancer therapy with antiestrogens

Current clinical research is focused upon the application of adjuvant therapy for the treatment of breast cancer. Combination chemotherapy is the most successful adjuvant therapy for premenopausal patients whereas the antiestrogen tamoxifen (1 or 2 yr) is successful in postmenopausal disease. We have developed a unifying strategy for the treatment of breast cancer. The thesis is based upon the application of continuous adjuvant therapy with tamoxifen in a low estrogen environment. Chemotherapy causes a chemical castration in premenopausal patients. In contrast, tamoxifen causes an increase in steroidogenesis. A combination of both approaches will work against each other until ovarian failure occurs. Patients should be checked for castration to provide a low estrogen environment in which tamoxifen, a competitive antagonist of estrogen action, can effectively work. Laboratory evidence using carcinogen-induced rat mammary tumor models demonstrates the efficacy of long-term therapy. Studies with the human breast cell line MCF-7 grown in athymic mice show that tamoxifen is a tumoristatic agent so that once the therapy is stopped, tumors can be regrown by estrogen administration. Patients should receive continuous tamoxifen therapy to prevent the growth-stimulating effects of adrenal steroids, environmental and phyto-estrogens.     

Carlo M. Croce: Seeking Truth and Beauty

Believe it or not, as a boy Carlo Croce liked to hang out in art museums, to his mother’s chagrin. There are a lot of art museums in Italy, so his mother started dropping him off and going off to the coffee bar to find more interesting company. He bought his first painting, an old master, at age 12 and that used all his savings. He didn't resume his old master collection until he was in his 30s and had saved some money from his job at the Wistar Institute in Philadelphia. He now has an exciting and growing collection.In the meantime, he received his MD degree from the University of Rome “La Sapienza” while reading textbooks and journals in English to supplement the old style medical education. He planned to join Karl Habel at Scripps Clinic in 1970 for a research fellowship just as Dr. Habel was struck in his prime by a monkey B virus infection, so Carlo was diverted from California to Philadelphia to join Hilary Koprowski's internationally known Wistar Institute of Anatomy and Biology. I was a Ph.D. student at Wistar at the time and witnessed the arrival of the quiet 25 yr. old Italian who was too shy to try out his textbook English.He began his work in somatic cell genetics and virology in a large laboratory where a number of us worked on related projects, including Barbara Knowles (now Associate Director for Research at Jackson Laboratory) and Davor Solter (now Director of Developmental Biology, Max Planck Institute, Freiburg, Germany).One of his first accomplishments was to map the very first viral integration site on chromosome 7q in an SV40 transformed fibroblast cell line, using human-mouse somatic cell hybrids that retained human chromosome 7, the SV40 T-antigen and the SV40 genome. Very recently, one of his hybrid clones was used by others to clone the SV40 genome integration site and to show that the SV40 genome had integrated into a common fragile site.Still using somatic cell hybrids, Carlo Croce and his laboratory began in the late 70s and early 80s to map genes important in cancer, such as the immunoglobulin genes that are rearranged in lymphomas, along with the MYC and BCL2 genes among others. These experiments took advantage of the leukemia/lymphoma specific translocation to walk from immunoglobulin loci, and later TCR loci, into the oncogene loci juxtaposed by translocation, the beginning of positional cloning of translocation breakpoints. These studies involved collaborations with valued colleagues, including Peter Nowell, the co-discoverer with David Hungerford, of the Philadelphia chromosome, the first reported cancer specific chromosome alteration. In the exciting decode of the 1980s, the Croce laboratory published 23 reports in Science, including the discovery of the BCL2 gene with Yoshiide Tsujimoto (now University of Osaka). They also observed that mistakes by immunoglobulin family rearrangement/recombination machinery was responsible for the type of chromosome translocations that involved the IG and TCR genes.Carlo Croce has been not only an outstanding laboratory scientist with numerous important discoveries to his credit; he has also been the Director of an NCI designated Cancer Center, first at the Fels Institute for Cancer Research, where he built a first class basic cancer research faculty from the ground up. In 1991, he moved his cancer research faculty to Jefferson Medical College, where it took the name of its benefactor, Sidney Kimmel, and became the Kimmel Cancer Center. At KCI the Croce laboratory continued to find and study genes involved in cancer development: oncogenes activated by translocation such as ALL1, involved in biphenotypic leukemias, discovered with another important collaborator, Eli Canaani and TCL1 (with Gianni Russo’s lab) activated by translocation to the TCRa locus in lymphomas of ataxia telangiectasia patients; or tumor suppressor genes, lost usually through deletions in epithelial cancers, such as FEZ1/LZTS1 at 8p22 lost in prostate, breast and other cancers and the FHIT gene at the 3p14.2 common fragile site (discovered in a collaboration with my laboratory), confirming a long held hypothesis that genes at chromosome fragile sites could contribute to cancer development through frequent chromosomal rearrangements. At the same time, Carlo Croce was living the nearly always tumultuous life of a Director of a Cancer Center, involving recruitment of faculty, constant bargaining with Deans, department chairman, University administrators, but he still manages to fit in a few skiing meetings, gossip sessions with colleagues like Web Cavenee, visits for good coffee, good food and TV appearances in his beloved Italy and most of all, he still manages to study, examine, buy, transport, restore, reframe and admire his old master paintings. I think he loves it as much as science because discovering a beautiful but misattributed painting at an obscure or even well known auction house, buying it and then proving that it is actually a painting by a Gentileschi or a Cavallino is as thrilling and elegant as discovering the connection between a specific gene alteration and its cancer.     

The fight against tamoxifen resistance in breast cancer therapy: a new target in the battle?

Tamoxifen is one of the most successful and widely used chemopreventive agents ever, and is an effective therapeutic agent for inhibiting growth of hormone receptor positive breast cancers. Tamoxifen and some of its metabolites bind to estrogen receptors and allow subsequent DNA binding at estrogen responsive genes, blocking some estrogenic signals while maintaining others, depending on the tissue. When used therapeutically for up to five years, cases of tamoxifen resistance appear, requiring alternative therapies. One recent proposal uniquely targets a zinc finger of the DNA binding domain of estrogen receptors, rather than the ligand binding domain, to circumvent resistance. In light of the most recent clinical data, however, it is now clear that aromatase inhibitors are the preferred first line therapy for all stages of breast cancer in post-menopausal women, whether they have had previous tamoxifen exposure or resistance.