Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 91-106).

Uterine leiomyomas are benign tumors within the uterus, where patients present with symptoms such as abnormal bleeding, urinary retention, and pelvic pressure. The exact etiology of uterine leiomyomas is unknown, but numerous theories have been proposed, indicating a multifactorial mechanism, including lifestyle and steroid hormones. Uterine leiomyomas have become a public health concern due to the high cost of treatment as well as the high prevalence within African American communities. Currently, many treatment options exist, ranging from conservative treatments that address symptoms, to surgical intervention to remove the uterus. Research efforts thus far have determined the relationship between the role of estrogen in the growth of uterine leiomyomas (which has led to development of medications that target different approaches to estrogen synthesis) and its effects in the pathogenesis. Studies have shown that estrogen acts on estrogen receptor subtypes, ER and ER. This study examines the role of these two receptors in estrogenic effects, and how these effects relate to the development of uterine leiomyomas. Available research has shown that each receptor has its unique functions and impacts the growth of tumors differently. There is conflicting evidence in how the number of receptors and surrounding environment modulate leiomyomas, with some studies reporting that it is the corepressors and/or coactivators that ultimately determine the influence of estrogenic effects. However, the general consensus of such studies suggests that estrogen receptor-specific therapeutic intervention is a novel area with great potential. The primary benefit of estrogen receptor-specific treatment, such as selective estrogen receptor modulators, is the ability to regulate physiological processes that contribute to the growth of uterine leiomyomas. Future directions of research include confirming the exact roles of ER and ER and harnessing the effects of their differing functions to manage uterine leiomyomas.

Endocrine resistance is a significant clinical problem in the treatment of estrogen (E2) receptor positive breast cancers. There are two ER subtypes, ERα and ERβ, which promote and inhibit breast cancer cell proliferation respectively. While ER positive breast cancers typically express a high ratio of ERα to ERβ, the acquisition of antiestrogen resistance in vitro and in vivo is associated with increased relative expression of the ERβ. On some gene enhancers ERβ has been shown to function in opposition to the ERα in the presence of E2. Here we demonstrate that exposure to two different ERβ agonists results in decreased cell viability, and produced a marked reduction in G2/M phase in antiestrogen resistant breast cancer cell line in conjunction with altered cyclin D1, and cyclin E expression relative to E2. ERβ agonists also strongly downregulated Bcl-2 expression and recruited both ERs to the Bcl-2 and pS2 E2-response elements resulting in a reduction in mRNA transcripts from both of these genes. Bcl-2 reduction correlated with increased lipidation of LC3-I to LC3-II, indicative of increased autophagic flux. Although ERβ agonist treatment alone did not induce apoptosis, remarkably, the coaddition of ERβ agonist and the autophagy inhibitor, chloroquine, resulted in robust cell death. Lastly, in vivo studies demonstrate that preferential-ERβ agonists are not estrogenic in the uterus or mammary gland. Together, these observations suggest that combined therapies including an ERβ agonist and an autophagy inhibitor may provide the basis for a safe, novel approach to the treatment of antiestrogen-resistant breast cancers.

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<p>Adenokarcinom prostate (PCa) je najče&scaron;ći karcinom u mu&scaron;karaca. Intraepitelne prostatične neoplazme visokog gradusa (HGPIN) su lezije koje prethode nastanku invazivnog karcinoma i podrazumevaju kompletno odsustvo bazalnih ćelija i invaziju strome malignim acinusima. Estrogeni receptor &beta; (ER&beta;) se nalazi u jedrima bazalnih i sekretornih ćelija acinusa i delimično u stromalnim ćelijama. Cilj istraživanja je da prikaže i lokalizuje ER&beta; u različitim morfolo&scaron;kim lezijama prostate: hiperplaziji (BHP), PINu i u PCa sa različitim Gleason scorom. Pretpostavlja se da prekancerozne lezije u svojim različitim fazama evolucije ne koreliraju u potpunosti sa ekspresijom ER&beta;. LGPIN pokazuje ekspresiju, dok u HGPINu nema ekspresije. Takođe je pretpostavka da ekspresija ER&beta; postoji u većine srednje diferentovanih PCa, te da se ekspresija posmatranog receptora gubi sa porastom Gleason scora. Ispitivano je pet grupa bolesnika:&nbsp; kontrolna grupa sa BHP i četiri eksperimentalne grupe (PIN i 3 različite grupe PCa). Studija je sprovedena na mu&scaron;karcima različite starosti u periodu 2010&ndash;2012. Nijedan pacijent nije prethodno primio hormonsku terapiju. Sekstant biopsije prostate su bojene na ER&beta; (Novocastra). Lokalizacija i intenzitet ER&beta; ekspresije prikazani su kroz skor: 0 = nula; 1 = &lt;1%; 2 = 1&ndash;10%; 3 = 11&ndash;33%; 4 = 34&ndash;66%; 5 = &gt; 66%. Pozitivni fibroblasti i endotelne ćelije su kori&scaron;ćene za poređenje. Smanjena ekspresija ER&beta; primećena je kod malignih i premalignih lezija prostate naspram BHP. Ekspresija ER&beta; u epitelnim ćelijama acinusa bila je najslabija u dobro diferentovanim PCa. Kod BHP i dobro diferentovanih PCa bila je veća ekspresija ER&beta; u bazalnim ćelijama nego u sekretornim. Lo&scaron;e diferentovani PCa prikazali su smanjenje ekspresije ER&beta; u bazalnim ćelijama. Ukupna ćelijska ekspresija ER&beta; predstavlja složen i ponekad moguće paradoksalan nalaz, na osnovu čega primarni PCa zadržava ekspresiju ovog receptora, ali ipak značajno nižu u poređenju sa benignim epitelom i premalignim lezijama. Ovaj nalaz podupire stanovi&scaron;te o antiproliferativnoj ulozi ER&beta; u tkivu prostate.</p> / <p>Adenocarcinoma of the prostate (PCa) is the most common cancer in men. High-grade prostatic intraepithelial neoplasia (HGPIN) are lesions that precede to invasive carcinomas and include complete absence of basal cells and stromal invasion by malignant acini. Estrogen receptor &szlig;(ER&szlig;) is located in the nuclei of basal and secretory cells and partly in stromal ones.The aim of the research is to describe and localize ER&szlig; in different morphological lesions: prostate hyperplasia (BPH), PIN and PCa with different Gleason score. It is assumed that pre-cancerous lesions in different stages of their evolution not correlate completely with the expression ER&szlig;. LGPIN shows expression, while there is no expression in HGPIN. It is also an assumption that the expression ER&szlig; exists in most medium differentiated PCa, and that the expression of this receptor loses with increasing of Gleason score. Five groups of patient were investigated: control group with BPH and four experimental groups (PIN and 3 different groups of PCa). The study was conducted on men of different ages in the period 2010-2012. None of the patients received prior hormonal therapy. Sextant prostate biopsy were stained on ER&szlig; (Novocastra). ER&szlig; expression is shown through the score: 0 = zero; 1 = &lt;1%; 2 = 1-10%; 3 = 11-33%; 4 = 34-66%; 5 =&gt; 66%. Positive fibroblasts and endothelial cells were used for comparison. Reduced expression was observed in malignant and premalignant lesions of the prostate versus BPH. ER&szlig; expression in the epithelial cells of acini was the weakest in well-differentiated PCa. In BPH and well differentiated PCa was greater expression in the basal cells than in secretory ones. Poorly differentiated PCa showed a decreased ER&szlig; expression in basal cells. Total cellular expression of ER&szlig; is a complex and sometimes paradoxical finding on the basis of which the primary PCa retains expression of this receptor, but significantly lower compared to benign epithelium and premalignant lesions. This finding supports the antiproliferative role of ER&szlig; in prostate tissue.</p>

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Introdução: Estimativas mostram que mais de dois terços das mulheres com câncer de mama possuem receptores hormonais positivos, e recebem terapia endócrina como tratamento, sendo tamoxifeno (TAM) o tratamento padrão (EBCTCG 2005; Davies et al., 2012). Porém, muitas pacientes se tornam resistentes com o passar do tempo. Estudos prévios mostraram que a expressão do receptor de estrogênio β (REβ) aumenta a resposta ao tratamento com TAM em células de câncer de mama, assim como a coexpressão de REα e REβ esta associada com maior ação proliferativa de TAM (Treeck et al., 2010; Sun et al., 2014). Também foi observada a existência de “cross-talk” entre os RE e a família do receptor do fator de crescimento epidérmico (HER) na resposta ao tratamento com TAM (Lindberg et al., 2011; Blows et al., 2010). Objetivo: Verificar a expressão do REβ, e suas interações com REα e receptores HER, durante o tratamento com TAM e em células resistentes ao TAM. Métodos: A expressão do REβ foi analisada em dois bancos de dados contendo informações de pacientes com câncer de mama. A expressão de RNAm dos RE, receptores HER e vias de sinalização PTEN, Akt e MAPK foram avaliadas após tratamento com TAM, em células resistentes ao TAM e em células silenciadas para os genes dos RE. Também foi avaliada a viabilidade celular após tratamento com TAM e nas células silenciadas para os genes dos RE. Resultados: Pacientes com câncer de mama apresentaram expressão reduzida do REβ, e os subtipos de câncer de mama REα positivos apresentaram baixa expressão do REβ quando comparados aos subtipos REα negativos. Células expressando níveis moderados de REβ apresentaram melhor resposta ao tratamento com TAM. Diminuição nos níveis dos RE é acompanhada por aumento nos níveis dos receptores ErbB2 e ErbB3, aumento de PTEN e diminuição de Akt e MAPK3 após tratamento com TAM. ERβ modula a ação antiproliferativa do TAM através da via de MAPK3. Células resistentes ao TAM apresentaram baixos níveis dos RE e altos níveis dos receptores EGFR, ErbB3 e ErbB4. Conclusão: Estes resultados demonstram que o REβ, e suas interações com REα e receptores HER, possuem papel importante na resposta ao tratamento com TAM. / Introduction: Approximately two-thirds of all breast cancer patients overexpress hormonal receptors, and are treated with endocrine therapy, being tamoxifen (TAM) the standard treatment. However many of initial responders to TAM as first-line experience relapse. Several mechanisms have been proposed to explain the occurrence of acquired TAM resistance. Previous studies showed that estrogen receptor β (ERβ) expression is associated with better response to tamoxifen treatment, as the co-expression of ERα and ERβ is associated with TAM antiproliferative effects. Moreover, there is growing interest about the cross-talk between ERs and ErbB family in response to endocrine therapy. Suggesting that TAM can acts through ERβ and/or ErbB family as compensatory pathways. Objective: To evaluate the expression of ERβ and the relation of ERβ with ERα and ErbB family in response to TAM treatment and in TAM resistant cells. Methods: ERβ expression was analyzed in two different databases of breast cancer patients. The mRNA levels of ER, HER receptors and PTEN, Akt and MAPK signal pathways were measured after TAM treatment, in TAM resistance cells and in cells silenced for ER genes. The cellular viability was also measured after TAM treatment, in TAM resistance cells and in cells silenced for ER genes. Results: Breast cancer patients presented reduced ERβ expression and the ERα-positive breast cancer subtypes presented lower ERβ levels when compared to ERα-negative breast cancer subtypes. Cells expressing moderates levels of ERβ presented better response to TAM treatment. Down-regulation of ERs induced by TAM treatment are accompanied with an increase in ErbB2 and ErbB3, reduced AKT and MAPK3 mRNA levels and increased PTEN levels. ERβ modulates TAM anti-proliferative effects through MAPK3 pathway. TAM– resistant cells expressed decreased ER mRNA levels and increased EGFR, ErbB3 and ErbB4 levels. Demonstrating that the cross-talk between ERs and HER family influence the response to TAM treatment. Conclusion: These results provide additional data indicating the importance of ERβ, and the relation with ERα and HER receptors, to predict TAM responsiveness.