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V J Assikis and V C Jordan

INTRODUCTION Tamoxifen, a non-steroidal antiestrogen, is the endocrine treatment of choice for breast cancer. Thousands of women worldwide start a course of tamoxifen therapy each year. Tamoxifen, initially prescribed for metastatic disease only, now constitutes the primary hormonal therapeutic approach for estrogen receptor-positive disease, regardless of stage and age (Jordan 1994). Although it exerts its primary antitumor actions by blocking the growth-promoting effects of the estrogens, tamoxifen also exhibits a spectrum of estrogenic and antiestrogenic properties in different tissues around the body. The estrogen-like action of tamoxifen on lipids and bones accounts for the decreased incidence of fatal myocardial infarction (McDonald & Stewart 1991) and preservation of bone respectively in postmenopausal women (Love et al. 1992). Tamoxifen prevents the development of mammary cancer in laboratory animals (Jordan 1976), and in clinical trials tamoxifen is noted to reduce contralateral breast cancer by 40% (EBCTCG 1992). These observations led to
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S A W Fuqua, C Wiltschke, C Castles, D Wolf, and D C Allred

ABSTRACT

We have isolated an estrogen-receptor (ER)-variant mRNA from ER-negative/progesterone receptor (PgR)-positive human breast cancers. This variant lacks exon 5 of the hormone-binding domain, resulting in a truncated receptor protein which is unable to bind estrogen. In vitro experiments show that the exon 5 variant possesses constitutive ER activity. For example, when transfected into ER-negative MDA-MB-231 breast cancer cells, it stimulates an estrogen-responsive element (ERE)-dependent reporter system in the presence or absence of exogenous hormone. Proliferation is unaffected by the antiestrogen tamoxifen, which usually inhibits the growth of MCF-7 cells, suggesting that the exon 5 variant may be important clinically in drug resistance. Preliminary studies have found expression of the exon 5 variant transcript in ER-positive breast cancers, but these studies need to be expanded to detect the protein in tumors. It is also possible that ER variants which influence cell proliferation may be involved in carcinogenesis. In this context, we have identified a novel ER variant in a preliminary survey of hyperplastic lesions which are thought to be precursors of invasive breast cancer. This variant possesses a single base-pair alteration in the hormone-binding domain, and exhibits enhanced stimulation of an ERE-reporter system when cotransfected into MDA-MB-231 breast cancer cells. We are currently evaluating its prevalence in premalignant breast lesions, and its ability to influence cell proliferation.

Endocrine-Related Cancer (1995) 2 19-25

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

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-α (ERα) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERα is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERα, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERα to the IGF-I and epidermal growth factor receptors. A major question is how ERα locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERα in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERα, serves as the ‘bus’ which carries ERα to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERα to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of ‘adaptive hypersensitivity’ and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.

Open access

Naomi E Allen, Timothy J Key, Laure Dossus, Sabina Rinaldi, Anne Cust, Annekatrin Lukanova, Petra H Peeters, N Charlotte Onland-Moret, Petra H Lahmann, Franco Berrino, Salvatore Panico, Nerea Larrañaga, Guillem Pera, Maria-José Tormo, Maria-José Sánchez, J Ramón Quirós, Eva Ardanaz, Anne Tjønneland, Anja Olsen, Jenny Chang-Claude, Jakob Linseisen, Mandy Schulz, Heiner Boeing, Eva Lundin, Domenico Palli, Kim Overvad, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Sheila Bingham, Kay-Tee Khaw, H Bas Bueno-de-Mesquita, Antonia Trichopoulou, Dimitiros Trichopoulos, Androniki Naska, Rosario Tumino, Elio Riboli, and Rudolf Kaaks

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case–control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50–4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20–3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98–2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88–2.36; P=0.05) and 2.05 (95% CI 1.23–3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34–0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

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B L Brockdorff, I Heiberg, and A E Lykkesfeldt

Development of antiestrogen resistance is a major clinical problem, and therefore it is crucial to elucidate the mechanisms involved. To investigate whether gain-of-function or loss-of-function mechanisms was most likely to be involved, cell fusion between the antiestrogen-sensitive MCF-7 and the ICI 164384- and ICI 182780-resistant MCF-7/164(R)-5 cell lines was performed. Furthermore, a fusion cell line between the tamoxifen-resistant MCF-7/TAM(R)-1 and the MCF-7/164(R)-5 cell line was established. A thorough investigation of growth parameters and expression of selected proteins (estrogen receptor-alpha (ERalpha), progesterone receptor (PR), Bcl-2, IGF-binding protein-2 (IGFBP2) and IGF receptor Ialpha (IGF-IRalpha)) in the fusion partners and fusion cells revealed that both gain- and loss-of-function changes occurred, and that the mechanisms resulting in resistance to the two antiestrogens were different. This multi-factoriality of antiestrogen resistance is promising in relation to sequential treatment of breast cancer patients with different types of endocrine therapy. Furthermore, we found an association between antiestrogen resistance and reduced IGF-IRalpha expression. Overall, the data presented in this report support the usefulness of cell fusion to clarify the mechanisms involved in development of resistance to the pure antiestrogens ICI 182780 and ICI 164384 and the selective ER modulator tamoxifen and suggest IGF-IRalpha as a new sensitive marker for response to antiestrogen treatment.

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S H Safe

Sir, This paper (Safe & McDougal 1997) briefly summarized a conference presentation (Current Topics in Breast Cancer Research, Cambridge, 1996) which focused primarily on organochlorine estrogens/antiestrogens (the major focus) and not on the research studies by Drs Bradlow, Telang and co-workers. Nevertheless, seven references to their research were included. This group has published several excellent studies on 2- and 16α-hydroxylation of 17β-estradiol (E2) and their possible role in various cancers. Based on results of our previous studies on the induction of CYP1A1 and related activities in MCF-7 cells (e.g. Harris et al. 1989, Chaloupka et al. 1992, Arellano et al. 1993; Moore et al. 1993, 1994, Liu et al. 1994), we reinvestigated the influence of mammary carcinogens and anticarcinogens on metabolism of E2 in this cell line. Ongoing studies in my laboratory showed that the mammary carcinogen benzo-[a]pyrene (BaP) induced CYP1A1 in MCF-7 cells and we
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J Huber and D Gruber

ABSTRACT

Patients with macrocysts have a two- to fourfold higher risk of developing breast cancer and should be monitored carefully while on hormone replacement therapy. Estradiol and progesterone seem to enhance the mitotic rate of breast cells and serum levels should be reduced to the lowest levels possible. Investigations are necessary to confirm the stimulatory effect of serum steroids on breast/cyst epithelial cells. The effect of norethisterone on breast tissues must also be considered. The conversion of norethisterone to ethinylestradiol may make this progestogen unsuitable for replacement therapy in breast cyst patients, but this requires conformation in clinical studies.

Recently it was demonstrated that cholic acids accumulate in breast cyst fluid and that their metabolism is influenced by sex steroids. Experimental and clinical studies are necessary to elucidate this breast-gut connection.

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E Levin, S Caruso, and A M Actis

It is accepted that quantitative determination of steroid receptors, useful as it is as a first indication of hormone dependence in mammary neoplasias, is insufficient to accurately characterize the tumor biology, especially for deciding clinical conduct. Functional assays provide one step towards insight on the integrity of receptor behavior, particularly the transcriptional modulation of proteins related to cell proliferation/differentiation. Progesterone receptor (PgR) expression is one such functional marker for estrogen receptors (ERs) and as a prognostic marker in mammary oncology it has contributed to an improvement in the proportion of correct clinical decisions. Protein-protein interactions among transcription factors are also the target of studies to correlate certain receptor functions with clinical outcome. Such interactions do not always result in quantitative changes of receptor function, but may involve qualitative modifications like translocations, mutations, isoforms and conformational changes, which could be reflected in the differing function of the receptor (Tora & Davidson
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Rosalinda M Savoy and Paramita M Ghosh

Estrogens were once used for the treatment of prostate cancer (PC). They may still be used in various parts of the world to that effect. Recent developments in the understanding of a role for estrogen receptor β (ERβ) in the development and progression of this disease resurrect the discussion on the intertwined roles of ERβ and the androgen receptor (AR) in promoting PC. A new article by Zellweger et al. in Endocrine-Related Cancer investigates the expression and assesses the activity of ERα and ERβ as well as the AR, in addition to a phosphorylated form of AR in hormone-naïve and castration-resistant PC.