Richard Santen

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..88 to 1.66 cm. Modeling of the biologic behavior of these occult tumors facilitates interpretation of tamoxifen breast cancer prevention and menopausal hormone therapy studies...

..Reports of androgen receptor mutations and historic clinical observations raised the hypothesis that estrogens might be involved in the proliferation of androgen-refractory prostate carcinoma...

..This effect can be abrogated by administration of the c-Src inhibitor, PP2 which also restores sensitivity to tamoxifen...

..With such assays, greater discrimination should be achievable when using estradiol levels as a predictor of the risks for breast cancer and for fractures...

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..Several pharmacological and clinical considerations suggest that GC/MS/MS should become the preferred method for monitoring aromatase inhibitor therapy...

..We have used a new downstream inhibitor of these pathways, farnesyl-thio-salicylic acid (FTS), to block proliferation in hypersensitive cells as a model for a potentially effective strategy for treatment of patients...

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..Taken together, these data suggest that both ER-dependent and genotoxic ER-independent effects of estradiol mediate breast cancer development...

..These data suggest that FTS is a promising agent to be developed for treatment of hormone-dependent breast cancer...

..Taken together, these observations suggest that the cell membrane ER pathway may be responsible for upregulation of MAP kinase and hypersensitivity in cells adapted to estradiol deprivation...

..Additional studies are now needed to determine the precise relationship between MAP kinase activation and tumor proliferation, apoptosis, and degree of invasiveness as well as on disease free and overall survival...

..To determine the lowest dosage of vaginally administered estradiol (E2) that reverses signs and symptoms of urogenital atrophy but does not substantially increase plasma E2 levels...

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..Recent comparative studies of these agents provide extensive data on fracture rates, bone mineral density, and markers of bone formation and resorption...

..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...

..No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement...

..In this review, the role of Shc in mediating estrogen effects on MAP Kinase regulation, cell growth and anti-apoptosis will be discussed. The possible role of PI3-kinase in estrogen rapid action is also reviewed in brief...

..Our results suggest that enhanced nongenomic function of ERalpha via cooperation with the EGFR pathway is one of the mechanisms responsible for acquired tamoxifen resistance...

..These observations suggest 1 mechanism whereby AIs, which block E(2) synthesis, would be more effective for breast cancer prevention than use of antiestrogens, which only block ER-mediated effects...

..Together, our data support the novel view that E2 can activate a linear pathway involving the sequential activation of IGF-IR, MMP, HB-EGF, EGFR, and MAPK...

..Together, these data demonstrate that culture of breast cancer cells under Pre-M and PM conditions and structurally diverse antiestrogens results in adaptive responses with differing biological signatures...

..Taken in aggregate, these studies suggest that secondary resistance to hormonal therapy results in usage of both IGF-R and EGF-R for non-genomic signaling...

..Our data suggest that TMS is a promising therapeutic agent because of its unique ability to block several pathways involved in the development of hormone resistance...

..Our data support the view that membrane-associated ERalpha is critical in estrogen-initiated MAPK activation...

..Thus, our findings indicate that FTS represents a new type of mTOR inhibitor, which acts by dissociating the functional mTOR-raptor signaling complex...

..The compound farnesylthiosalicylate (FTS), a specific antagonist of the 21 kDa Ras protein, suppresses GF signaling and it might be a useful therapy against advanced PCa...

..Whether this translates into better body composition and metabolic outcomes in girls with hypogonadism is being actively investigated and data will soon be available...

..A full understanding of the mechanisms underlying these relationships, with the ultimate aim of abrogating specific steps, should lead to more-targeted strategies for treatment of hormone dependent-breast cancer...

..Together, our results demonstrate that Shc and IGF-1R serve as key elements in the translocation of ERalpha to the cell membrane and in the facilitation of ERalpha-mediated rapid E2 action...

..These hypotheses regarding oestrogen-induced apoptosis in the short term and carcinogenesis in the long term now require rigorous verification but would serve to explain the "oestrogen paradox"...

..Each pathway represents a potential target for blocking cell migration and metastasis of breast cancer cells...

..In support of this possibility, LTED and TGFalpha-treated wild-type cells were hypersensitive to the effects of E(2) on the key cell cycle regulator, E2F1...

..Our results suggest that different mechanisms are involved in acquired endocrine resistance and the necessity for individualized treatment of recurrent diseases...

..Our data suggest that in addition to the MAP kinase pathway, activation of the PI3 kinase pathway is involved in E2 hypersensitivity, which develops during adaptation of MCF-7 cells to the low estrogen environment...

..These later data provide support for the concept that FTS exerts its effects predominantly by blocking mTOR and to a lesser effect by inhibition of MAP kinase in breast cancer cells...

..The E2-induced morphological changes were prevented by antiestrogen. Together our results demonstrate that ERalpha can mediate the rapid effects of E2 on Shc, MAPK, Elk-1, and morphological changes in breast cancer cells..

..This retrospective study systematically compared mammographic density with histology in women receiving or not receiving menopausal hormone therapy (HT)...

..Understanding the mechanisms underlying these relationships, with the aim of abrogating specific steps, should lead to more targeted strategies to treat hormone-dependent breast cancer...

..A full understanding of the mechanisms underlying these relationships with the ultimate aim of abrogating specific steps, should lead to more targeted strategies for treatment of hormone-dependent breast cancer...

..However, we conclude from our analysis that the burden of proof regarding progestins has now shifted. One must now prove that an estrogen/progestin combination is safe with respect to breast cancer rather than having to prove it harmful...

..These results provide validation for the RCUB in postmenopausal women and suggest that it might prove useful for selection of women for drug therapy to prevent breast cancer...

..These findings support the possibility that aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer...

..Mammographic breast density therefore needs to be examined in further detail in order to better assess the risks of breast cancer in postmenopausal women and further individualize prescribing practices...

..The human assay was sufficiently sensitive to detect aromatase in a single human JAR (choriocarcinoma) cell, in all breast biopsies measured, and in 7/23 ductal lavage fluids...

..The BCPCG analyzed potentially available clinical material from previous prospective studies and determined that a large case/control study to evaluate these new factors might be feasible at this time...

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..Their use is sometimes extended to younger women after chemotherapy-induced amenorrhoea; we have audited this in one institution's breast unit, and we propose guidelines for use in such circumstances...

..These studies provide evidence that long-term TAM exposure enhances sensitivity to the estrogenic effects of TAM and also to E(2) itself...

..These criteria would allow validation of sensitivity, specificity, precision, and accuracy of current steroid hormone assay methodology and provide surrogates until a true gold standard can be developed...

..Our findings imply that demethylation of promoter C region in the ERalpha gene is in part responsible for the enhanced expression of ERalpha gene in LTED cells...

..Thus, although both CYP19 and CYP1B1 are expressed in a high percentage of breast cancers, CYP1B1 is not a major determinant of the disposition of AIs...

..A clinical trial in women, which is designed to specifically demonstrate that high dose estrogen induces tumor regression through the mechanism of apoptosis will be conducted. ..

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..The applicant expects these studies to be the basis for future clinical trials. ..

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..FTS, a novel mTOR inhibitor will be used in vitro to activate the stress kinase pathway and apoptosis. In vivo, FTS will be used to enhance estradiol induced apoptosis in nude mice. ..