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I Számel, B Budai, K Daubner, J Kralovánszky, Sz Ottó, J Tóth, and I Besznyák

ABSTRACT

Gross cystic disease (GCD) of the breast may be associated with a higher risk for the development of breast cancer. High levels of sex steroids, steroid hormone precursors, prolactin and cations have been found in breast cyst fluid (BCF) by several investigators. Accordingly, endocrine parameters and the cationic composition of BCF may be considered as useful characteristics to follow patients bearing macrocysts. In this study we have investigated the concentrations of estradiol (E2), progesterone, testosterone, dehydroepiandrosterone (DHA) and DHA-3-sulfate (DHA-S), prolactin, potassium (K+) and sodium (Na+) in BCF aspirated from 99 women. The mean age of the patients was 49.8 years (range 32-58). The hormone levels were measured by RIA methods; K+ and Na+ were determined by flame photometry. Estradiol, progesterone, testosterone, DHA, DHA-S, prolactin and K+ showed significant accumulation in the BCF compared with their respective serum values. The K+/Na+ ratio proved to be useful in dividing cysts into type I (≥1), type II (<1 but ≥0.1) and type III (<0.1) subgroups. For type I BCF, higher DHA, DHA-S and prolactin concentrations were detected. Linear regression analysis established a highly significant (P<0.001) correlation between the concentrations of E2 and DHA-S (r=0.686), and also between testosterone and DHA-S (r=0.711). These findings indicate that type I BCF might be a marker for 'active' GCD of the breast, and suggest that it may be associated with an increased breast cancer risk, since this group of patients is supposed to have cysts with apocrine metaplasia. It is suggested therefore that when BCF is aspirated, sex steroids, steroid precursors and cations should be routinely measured, and women with type I cysts should be regularly examined.

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V C Jordan, W L Catherino, and D M Wolf

INTRODUCTION Tamoxifen is the endocrine treatment of choice for all stages of breast cancer (Jordan 1993). The adjuvant use of tamoxifen produces survival advantages and prevents the appearance of a second primary breast cancer (Early Breast Cancer Trialists' Collaborative Group 1992). Nevertheless, the extended use of tamoxifen will be expected to produce drug resistance. A knowledge of the mechanisms of drug resistance will not only allow the development of new, and perhaps more effective, therapies but also may provide novel drug targets for new treatment strategies. MULTIPLE MECHANISMS FOR RESISTANCE TO TAMOXIFEN It is unlikely that there will be a single mechanism of drug resistance to tamoxifen. Multiple mechanisms may operate at different times to provide a growth advantage for the tumor. The fact that tamoxifen is a competitive inhibitor of estrogen action at the estrogen receptor has focused attention on receptor-mediated mechanisms of resistance. In
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Leigh C Murphy, Srinivas V Seekallu, and Peter H Watson

Multiple sites of phosphorylation on human estrogen receptor α (ERα) have been identified by a variety of methodologies. Now with the emerging availability of phospho-site-specific antibodies to ERα, the relevance of phosphorylation of ERα in human breast cancer in vivo is being explored. Multiple phosphorylated sites in ERα can be detected in multiple breast tumor biopsy samples, providing evidence of their relevance to human breast cancer in vivo. Published data suggest that the detection in primary breast tumors of phosphorylation at some sites in ERα is associated with a better clinical outcome while phosphorylation at other sites is associated with a poorer clinical outcome most often in patients who have been treated with tamoxifen. This suggests the hypothesis that phospho-profiling of ERα in human breast tumors to establish an ‘ERα phosphorylation code’, may be a more accurate marker of prognosis and/or response to endocrine therapy in human breast cancer.

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Takashi Suzuki, Yasuhiro Miki, Yasuhiro Nakamura, Takuya Moriya, Kiyoshi Ito, Noriaki Ohuchi, and Hironobu Sasano

It is well known that sex steroids are involved in the growth of breast cancers, and the great majority of breast carcinomas express estrogen (ER), progesterone (PR), and androgen (AR) receptors. In particular, recent studies have demonstrated that estrogens and androgens are locally produced in breast carcinoma tissues, and total blockade of in situ estrogen production potentially leads to an improvement in prognosis of breast cancer patients. Therefore, it is important to obtain a better understanding of sex steroid-producing enzymes in breast carcinoma tissues. In this review, we summarize recent studies on the expression and regulation of enzymes related to intratumoral production of estrogens (aromatase, 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1), and steroid sulfatase (STS) etc) and androgens (17βHSD5 and 5α-reductase) in human breast carcinoma tissues, and discuss the biological and/or clinical significance of these enzymes. The cellular localization of aromatase in breast carcinoma tissues still remains controversial. Therefore, we examined localization of aromatase mRNA in breast carcinoma tissues by laser capture microdissection/real time-polymerase chain reaction. Aromatase mRNA expression was detected in both carcinoma and intratumoral stromal cells, and the expression level of aromatase mRNA was higher in intratumoral stromal cells than in carcinoma cells in the cases examined. We also examined an association among the immunoreactivity of enzymes related to intratumoral estrogen production and ERs in breast carcinoma tissues, but no significant association was detected. Therefore, the enzymes responsible for the intratumoral production of estrogen may not always be the same among breast cancer patients, and not only aromatase but also other enzymes such as STS and 17βHSD1 may have important therapeutic potential as targets for endocrine therapy in breast cancer patients.

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Vera Cappelletti, Manuela Gariboldi, Loris De Cecco, Sara Toffanin, James F Reid, Lara Lusa, Emilio Bajetta, Luigi Celio, Marco Greco, Alessandra Fabbri, Marco A Pierotti, and Maria Grazia Daidone

This study aimed to define a gene expression profile associated with response to anti-estrogen treatment in estrogen receptor α (ERα)-positive breast cancer from elderly patients and to identify possible candidate genes associated with resistance by detecting those modulated by treatment. Using cDNA microarrays containing 16 702 unique clones, 21 pre-treatment and 11 paired post-treatment samples collected in a neo-adjuvant toremifene trial on elderly patients with operable and locally advanced ERα-positive breast cancer were profiled. Gene expression profiles generated from pre-treatment samples were correlated with treatment-induced tumor shrinkage and compared with those obtained from post-treatment paired samples to define genes differentially modulated following anti-estrogen treatment. Correlation analysis on 21 pre-treatment samples highlighted 53 genes significantly related to treatment response (P<0.001). Genes involved in cell cycle and proliferation were more frequently upregulated in responders compared with non-responders. Class comparison analysis identified 101 genes significantly modulated independently of treatment response; 82 genes were modulated in non-responders, whereas only 8 genes were differently expressed after treatment in responders. Gene expression profiles appear to be more frequently modulated by anti-estrogen treatment in non-responding patients and may harbor interesting genes possibly involved in anti-estrogen resistance, including clusterin, MAPK6, and MMP2. This concept was corroborated by in vitro studies showing that silencing of CLU restored toremifene sensitivity in the ER anti-estrogen-resistant breast cancer cell line T47D. Integration between neo-adjuvant therapy and transcriptional profiling has therefore the potential to identify therapeutic targets to be challenged for overcoming treatment resistance.

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Maxy De los Santos, Olaia Martínez-Iglesias, and Ana Aranda

Anti-estrogens are the current endocrine therapy of choice in the treatment of estrogen receptor (ER)-positive breast cancers. Histone deacetylase inhibitors (HDACi) also constitute a promising treatment for therapy, and combination of anti-estrogens with HDACi may improve efficacy while reducing side effects. We have examined the effect of the HDACi sodium butyrate and suberoylanilide hydroxamic acid (SAHA), alone and in combination with 17β-estradiol (E2) and the pure anti-estrogen ICI 182.780 (ICI) in human MCF-7 breast cancer cells. HDACi caused a sustained increase of histone H3 acetylation and caused cell death as shown by flow cytometry analysis. In surviving cells, both inhibitors were even stronger than ICI in depleting cyclin D1 levels, inducing expression of the cyclin kinase inhibitor p21Waf1/Cip1, blocking phosphorylation of the retinoblastoma protein, or inhibiting cell growth. No additive effects of ICI with either butyrate or SAHA were found. In addition, these drugs were able to antagonize the effects of E2 on expression of cell cycle proteins, cell growth, and transcription of ER-dependent genes. The anti-estrogenic effects of HDACi appear to be related to a strong downregulation of the expression of ERα that appears to be secondary to both transcriptional and post-transcriptional regulation. ERα phosphorylation is involved in estrogen signaling, and HDACi also prevented receptor phosphorylation in Ser-118 both in the absence and presence of ER ligands. These results provide further support for the use of deacetylase inhibitors as chemotherapeutic agents in the treatment of breast cancer tumors.

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Adam W Nelson, Wayne D Tilley, David E Neal, and Jason S Carroll

Prostate cancer is the commonest, non-cutaneous cancer in men. At present, there is no cure for the advanced, castration-resistant form of the disease. Estrogen has been shown to be important in prostate carcinogenesis, with evidence resulting from epidemiological, cancer cell line, human tissue and animal studies. The prostate expresses both estrogen receptor alpha (ERA) and estrogen receptor beta (ERB). Most evidence suggests that ERA mediates the harmful effects of estrogen in the prostate, whereas ERB is tumour suppressive, but trials of ERB-selective agents have not translated into improved clinical outcomes. The role of ERB in the prostate remains unclear and there is increasing evidence that isoforms of ERB may be oncogenic. Detailed study of ERB and ERB isoforms in the prostate is required to establish their cell-specific roles, in order to determine if therapies can be directed towards ERB-dependent pathways. In this review, we summarise evidence on the role of ERB in prostate cancer and highlight areas for future research.

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W-D Han, Y-L Zhao, Y-G Meng, L Zang, Z-Q Wu, Q Li, Y-L Si, K Huang, J-M Ba, H Morinaga, M Nomura, and Y-M Mu

Previous studies have shown that leukemia related protein 16 (LRP16) is estrogenically regulated and that it can stimulate the proliferation of MCF-7 breast cancer cells, but there are no data on the mechanism of this pathway. Here, we demonstrate that the LRP16 expression is estrogen dependent in several epithelium-derived tumor cells. In addition, the suppression of the endogenous LRP16 in estrogen receptor α (ERα)-positive MCF-7 cells not only inhibits cells growth, but also significantly attenuates the cell line’s estrogen-responsive proliferation ability. However, ectopic expression of LRP16 in ERα-negative MDA-MB-231 cells has no effect on proliferation. These data suggest the involvement of LRP16 in estrogen signaling. We also provide novel evidence by both ectopic expression and small interfering RNA knockdown approaches that LRP16 enhances ERα-mediated transcription activity. In stably LRP16-inhibitory MCF-7 cells, the estrogen-induced upregulation of several well-known ERα target genes including cyclin D1 and c-myc is obviously impaired. Results from glutathione S-transferase pull-down and coimmunoprecipitation assays revealed that LRP16 physically interacts with ERα in a manner that is estrogen independent but is enhanced by estrogen. Furthermore, a mammalian two-hybrid assay indicated that the binding region of LRP16 localizes to the A/B activation function 1 domain of ERα. Taken together, these results present new data supporting a role for estrogenically regulated LRP16 as an ERα coactivator, providing a positive feedback regulatory loop for ERα signal transduction.

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R J Santen, R X Song, Z Zhang, R Kumar, M-H Jeng, S Masamura, W Yue, and L Berstein

Clinical observations suggest that human breast tumors can adapt to endocrine therapy by developing hypersensitivity to estradiol (E(2)). To understand the mechanisms responsible, we examined estrogenic stimulation of cell proliferation in a model system and provided in vitro and in vivo evidence that long-term E(2) deprivation (LTED) causes "adaptive hypersensitivity". The enhanced responses to E(2) do not involve mechanisms acting at the level of transcription of estrogen-regulated genes. We found no evidence of hypersensitivity when examining the effects of E(2) on regulation of c-myc, pS2, progesterone receptor, several estrogen receptor (ER) reporter genes, or c-myb in hypersensitive cells. Estrogen deprivation of breast cells long-term does up-regulate both the MAP kinase and phosphatidyl-inositol 3-kinase pathways. As a potential explanation for up-regulation of these signaling pathways, we found that ERalpha is 4- to 10-fold up-regulated and co-opts a classic growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. E(2) binds to cell membrane-associated ERalpha, physically associates with the adapter protein SHC, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which results in the rapid activation of MAP kinase. These non-genomic effects of E(2) produce biological effects as evidenced by Elk activation and by morphological changes in cell membranes. Further proof of the non-genomic effects of E(2) involved use of cells which selectively expressed ERalpha in the nucleus, cytosol and cell membrane. We created these COS-1 "designer cells" by transfecting ERalpha lacking a nuclear localization signal and containing a membrane localizing signal. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. Adaptive hypersensitivity would explain the superiority of aromatase inhibitors over the selective ER modulators (SERMs) for treatment of breast cancer. The development of highly potent third-generation aromatase inhibitors allows reduction of breast tissue E2 to very low levels and circumvents the enhanced sensitivity of these cells to the proliferative effects of E(2). Clinical trials in the adjuvant, neoadjuvant and advanced disease settings demonstrate the greater clinical efficacy of the aromatase inhibitors over the SERMs. More recent observations indicate that the aromatase inhibitors are superior for the prevention of breast cancer as well. These observations may be explained by the hypothesis that estrogens induce breast cancer both by stimulating cell proliferation and by their metabolism to genotoxic products. The SERMs block ER-mediated proliferation only, whereas the aromatase inhibitors exert dual effects on proliferation and genotoxic metabolite formation.

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P E Goss

Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.