In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown. In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes. In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade. In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence. In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.

<b>Introduction:</b> Almost 7,000 people are diagnosed with ductal carcinoma in situ (DCIS) in the United Kingdom each year, but there remains uncertainty regarding its natural history and optimal management. The aim of this thesis was to evaluate factors contributing to the epidemiology of DCIS and its outcomes. <b>Methods:</b> 1) A cohort study comparing risk factors for DCIS and invasive breast cancer (IBC) using UK Biobank; 2) A cohort study examining the accuracy of preoperative biopsy in DCIS using clinical records from the Netherlands Cancer Institute; 3) A cohort study examining the rate of invasive breast cancer following treatment for screen-detected DCIS in England using the National Health Service Breast Screening Programme (NHSBSP) audit; 4) A methodological study to develop an algorithm to identify invasive breast cancer recurrences, which in the future may used to identify DCIS recurrences, using all relevant routinely collected data stored within Public Health England (PHE). <b>Results:</b> (1) For both DCIS and IBC, postmenopausal BMI was associated with an increased risk of developing disease, and the number of live births was associated with a decreased risk of developing disease. However, the magnitude of the effect differed between DCIS and IBC. The increased risk from postmenopausal BMI &GE;35 kg/m² was larger for DCIS than for IBC (RR 2.35, 95% CI 1.14-4.82), and the trend of reduction in risk with each additional live birth was greater for DCIS than for IBC (p for trend = 0.03). (2) Consideration of mammographic lesion size and the absence of necrosis on biopsy may be helpful in selecting low-risk women for non-operative management of DCIS in the future, as may use of the 9G vacuum-assisted method of biopsy. (3) The cumulative risks of IBC at 5, 10 and 15 years after screen-detected DCIS in England were 3.5%, 7.1%, and 9.4% respectively. Women with clear surgical margins of 1-2 mm had a higher IBC rate than women with clear margins of 5+ mm (RR 1.85, 95% CI 1.20-2.84). Women given breast-conserving surgery (BCS) without radiotherapy had a higher ipsilateral IBC rate than women given BCS with radiotherapy (RR 1.63, 95% CI 1.27-2.10). Women given hormone therapy had a lower rate of any IBC compared with oestrogen receptor (ER) positive women not given hormone therapy (RR 0.76, 95% CI 0.63-0.93). (4) There was good agreement between the number of recurrences indicated by the developed algorithm using routinely collected data sources and the number of recurrences recorded in the test dataset. This finding supports the potential value of compiling recurrence information on a nationwide basis from routinely collected data, for use in future descriptive and epidemiological studies and in follow-up for randomised trials. <b>Conclusions:</b> Using a variety of methods these studies have all succeeded in adding to knowledge about the epidemiology of DCIS. This knowledge can be used to help the future management of women with DCIS. In addition, each of the studies has planned extensions and will continue to contribute further knowledge periodically into the future.

Alterations to the tumour microenvironment is a common feature of many cancers, including breast cancer, and there is increasing evidence that alterations to the microenvironment, including; increased integrin expression, ECM deposition and protease activity, promote cancer progression. Most invasive breast cancers arise from a preinvasive stage, ductal carcinoma in situ (DCIS). Previous work in our laboratory has shown the microenvironment of DCIS is altered, such that myoepithelial cells (MECs) switch to a tumour-promoting phenotype, associated with upregulation of integrin αvβ6 and fibronectin (FN) expression. Mechanisms by which integrin αvβ6 and FN expression are regulated is unclear. We show DCIS progression into invasion is accompanied by an increase in MEC expression of integrin αvβ6 and periductal FN deposition, and their expression were associated in DCIS. These findings were modelled in isolated primary DCIS-MECs, primary normal MECs and MEC lines, with and without integrin αvβ6 expression, where integrin αvβ6-positive MECs upregulating FN expression. We identified integrin αvβ6-positive DCIS ducts were larger than integrin αvβ6-negative DCIS ducts, and mechanical stretching of primary normal MECs and a normal MEC line led to upregulation of integrin αvβ6 expression and FN deposition in a TGFβ-dependent manner. We further show upregulation of integrin αvβ6 and FN by MECs mediate TGFβ-dependent upregulation of MMP13 which promotes breast cancer cell invasion in vitro. These data show altered tissue mechanics in DCIS and MEC expression of integrin αvβ6 and FN deposition are linked, and implicate TGFβ in their activation. These findings suggest integrin αvβ6 and FN may be used as markers to stratify DCIS patients.

Elevated level of lipogenic enzymes and overall lipogenesis have been reported in a wide variety of cancers and blocking the lipogenic pathway by chemical inhibitors or RNA interference causes tumor cell death by apoptosis which provides a strong rationale for targeting lipogenic pathway for the treatment and prevention of cancer however the exact role of lipogenesis as a cause, facilitator or consequence is not yet clearly understood. Therefore in this dissertation research, we set up to determine the mechanism of tumor cell death by inhibiting lipogenesis and to determine the role of increased lipogenesis in the breast cancer progression. In the first part of this study, we investigated the status of fatty acid synthase (FAS) gene which is regarded as the key lipogenic gene in fatty acid biosynthetic pathway and is responsible for the synthesis of lipid molecules by facilitating the condensation reaction between acetyl-CoA and malonyl-CoA in the presence of NADPH. We observed that normal breast epithelial cells MCF10A cells have very low level of FAS expression whereas breast cancer cell lines MCF7, MDA MB231 and MDA MB231 LM have significant overexpression. Next, we observed the similar trend of FAS overexpression in breast cancer stem-like cells (CSCs) isolated from the MCF7, MDA MB231 and MDA MB231 LM cell lines using cell surface markers (CD24-/CD44+/ESA+). These cells were previously transplanted into the mammary fat pad of nude mice and the results of our limiting dilution analysis indicate that CSCs had a significantly higher ability of forming breast cancer in the injected animals which explains our rationale to use CSCs in our research. In order to exploit this lipogenic pathway for the treatment and chemoprevention of breast cancer, we then examined the effects of resveratrol on breast cancer cells. Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. We observed that resveratrol significantly reduced the cell viability by inducing apoptosis in parental cells as well as in CSCs. Resveratrol also inhibited mammosphere formation which is an inherent property of CSCs. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the FAS gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by FAS overexpression suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of CSC in an animal model of human breast cancer xenograft without showing apparental toxicity. Taken together, our results indicate that resveratrol is capable of inducing apoptosis in the CSCs through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol. Taken together, our results indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol. In the second part of research, we tried to determine the role of elevated level of lipogenesis in normal to ductal carcinoma in situ (DCIS) progression. For this, we first analyzed the expression profile of various lipogenic genes using an expression microarray and found that CSCs from DCIS.com showed significantly higher level of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and FAS than the normal non-tumorigenic stem-like cells obtained from MCF10A. The result was also confirmed by qRT-PCR and Western blot as well as in clinical specimens of DCIS by immunohistochemistry. In the next step, we detected that SREBP1, the master regulator of lipogenic genes, is also upregulated in DCIS and further identified that SREBP1 regulates the co-ordinate expression of ACLY, ACC and FAS ultimately resulting in the elevation of lipogenesis. In order to determine the role of SREBP1 overexpression in normal to DCIS transition, we overexpressed the SREBP1 in MCF10A cells which induced a significant increase in the downstream key lipogenic genes ACLY, ACC1 and FAS which resulted in the clear upregulation of total lipid content in the cells. Furthermore, we found that this elevation of lipogenesis in MCF10A-SREBP1 stem-like cells confers proliferative advantage as well as a significant increase in mammosphere forming ability and anchorage independent growth (3D culture). Thus, our results showed a possibility that increased lipogenesis in normal stem-like cells may be responsible for providing oncogenic transformation properties which can be confirmed at least in our in vitro model. We then examined the effects of resveratrol on CSCs sorted from DCIS.com. We found that resveratrol decreased the cell viability and increased apoptosis by reducing the total lipid content by inhibiting the expression of SREBP1 and downstream lipogenic genes. Resveratrol also hindered the stemness of the DCIS CSCs by inhibiting its mammosphere forming ability. When DCIS CSCs were transplanted into mammary fat pad of nude mice which were on resveratrol treatment, we observed that resveratrol significantly suppressed the formation of DCIS by downregulating lipogenic genes and by upregulating pro-apoptotic genes, DAPK2 and BNIP3. Collectively, our results indicate that lipogenic genes SREBP1 co-ordinately regulates the overexpression of ACLY, ACC1 and FAS in DCIS CSCs at an early stage of breast tumorigenesis and thus confer proliferative and survival advantages. Anti-growth effect of resveratrol on DCIS CSCs also provides us with a strong rationale to use this agent for chemo-prevention against DCIS.

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No. of bitstreams: 2 Dissertação - Nayara Alves de Freitas Lemos - 2015.pdf: 1558373 bytes, checksum: f3d20ea70bfd08864a3c3eaae4b69cad (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-07-17 / Objective: To analyze the temporal evolution of DCIS in residents of Goiânia during the period 1994-2010. Methods: It used the database of the Population Based Cancer Registries of Goiania (RCBPGo), cases coded as carcinoma in situ of the breast in females, at (ONCOSIS) program in Goiânia, between 1994 and 2010. It was later made individual search of histopathological reports of DCIS. We sought to identify the temporal evolution of standardized and crude incidence of DCIS. The incidence rates, crude, as standard, set by the global population Doll, were calculated by age groups to 10 years from 30 years, and was estimated to MPMA using Poisson Regression to these age groups. They calculated the disease-free survival and overall survival at 60 and 120 months, using the Kaplan-Meier method. The data on DCIS deaths were obtained from the Mortality Data System (SIM), the medical record information and the electoral higher court (TSE). Results: In the initial database were recorded 376 cases of DCIS. In reviewing the reports, 114 cases were excluded because it is not dealt with DCIS. Of the 282 cases of DCIS in the period studied, there were four cases in 1994 and 21 in 2010. The crude rate of annual incidence of DCIS was 1.33/100,000 in 1994, and of 4.21/100,000 in 2010. The adjusted incidence for the world population Doll was 0.58/100,000 in 1994, and of 1.85/100,000 in 2010. The average annual percentual change (AAPC) of the crude incidence rate for the period was 11.93% per year (95 9-15% CI; P <0.01) and standardized incidence rate of 11.94% per year (95% CI 9-15; p <0.01). There were 17 cases of local recurrence, 16 invasive ductal carcinomas and only one case of in situ recurrence. Three cases evolved with distant metastases. The cumulative rate of local recurrence was 3,9% at 60 months and 10% to 120 months. Overall survival was 96,5% and 91,9% at 60 and 120 months, respectively. The cancer-specific survival was 99,5% at 60 months and 98,4% at 120 months. Abstract xvii Conclusions: The study showed that there are a large number of cases that need to be recoded by changing the initial bank. Thus, we suggest that the highest injury potential aggressiveness is described first, standardized reports and the training of collectors, so there are no unknown information to transcribe the DCIS for RCBP the chips. There was an increasting incidence of DCIS rate in Goiânia, possibly related to mammographic screening. Despite the small number of local recurrences when appeared they arose mostly with invasion. Still, it was confirmed in the studied group high overall survival rate after 10 years of treatment. / Objetivo: Analisar a evolução temporal do carcinoma ductal in situ em moradores de Goiânia durante o período de 1994 a 2010. Métodos: Trata-se de um estudo descritivo retrospectivo de série temporal dos casos de carcinoma ductal in situ, no sexo feminino, em Goiânia, registrados no banco de dados do Registro de Câncer de Base Populacional dessa cidade no período entre 1994 a 2010. Posteriormente, realizou-se busca individual dos laudos histopatológicos de carcinoma ductal in situ para identificar a evolução temporal do carcinoma ductal in situ. As taxas de incidências, tanto bruta, quanto padronizada, ajustada pela população padrão, foram calculadas por grupos etários a cada 10 anos, a partir de 30 anos, e calculou-se a mudança percentual da média anual utilizando-se a regressão de Poisson. Para a análise de sobrevida global foi realizada busca ativa das pacientes no Sistema de Informações em Mortalidade, nas informações do prontuário médico e no Tribunal Superior Eleitoral. Foram calculadas a sobrevida livre de doença e a sobrevida global em 60 e 120 meses, pelo método de Kaplan-Meier. Resultados: No banco de dados inicial foram registrados 376 casos de CDIS. Na revisão dos laudos, foram excluídos 114 casos, pois não faziam parte dos critérios de inclusão. Dos 262 casos em Goiânia no período estudado, houve quatro casos em 1994 e 21 em 2010. A taxa bruta de incidência anual de CDIS foi 1,33/100.000 em 1994, e de 4,21/100.000 em 2010. Já a incidência ajustada para a população padrão foi de 0,58/100.000 em 1994, e de 1,85/100.000 em 2010. A mudança percentual da média anual da taxa de incidência bruta para o período foi de 11,93% ao ano (95% IC 9-15; p<0,01) e da taxa de incidência padronizada de 11,94% ao ano (95% IC 9 - 15; p<0,01). Houve 1 7 casos de recidiva local, sendo 1 6 carcinomas ductal invasores e apenas um caso de recidiva in situ. Três casos evoluíram com metástases à distância. A taxa cumulativa de recidiva local foi de 3,9% aos 60 meses e de 10% aos 120 meses. A sobrevida global Resumo xv foi de 96,5% e de 91,9% aos 60 e 120 meses, respectivamente. A sobrevida câncer-específica foi de 99,5% aos 60 meses e de 98,4% aos 120 meses. Conclusões: o trabalho mostrou um grande número de casos que precisam ser recodificados, alterando o banco inicial. A sugestão é que os laudos histopatológicos descrevam primeiramente a lesão de mais alto potencial de agressividade. É necessária uma padronização dos laudos, e a partir daí, o treinamento dos coletadores, para que não haja informações desconhecidas ao transcrever o CDIS para as fichas do RCBPGo. Foi constatado o aumento da taxa de incidência do CDIS na cidade de Goiânia, possivelmente relacionado à melhora do rastreamento mamográfico. E apesar do pequeno número de recidivas locais, quando apareciam, surgiam na sua grande maioria com invasão. Ainda assim, confirmou-se no grupo estudado alta taxa de sobrevida global após 10 anos do tratamento.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18128号 / 医博第3848号 / 新制||医||1001(附属図書館) / 30986 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福山 秀直, 教授 戸井 雅和, 教授 平岡 眞寛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Changes in the microenvironment have been implicated in the transition of pre-invasive ductal carcinoma in-situ (DCIS) to invasive breast cancer. Normal myoepithelial cells have a tumour suppressor phenotype but they are altered in DCIS and ultimately lost with transition to invasive cancer. A consistent change in DCIS is up-regulation of the integrin αvβ6 in myoepithelial cells. Preliminary observations identified a correlation between myopeithelial αvβ6 and an increased peri-ductal inflammatory infiltrate. The hypothesis of this study is that the altered myoepithelial phenotype influences the peri-ductal inflammatory environment, which in turn mediates a pro-apoptotic effect on myoepithelial cells contributing to their loss. To investigate this, the inflammatory infiltrate was characterised in a series of DCIS tissue in relation to αvβ6 status. This demonstrated significantly higher levels of CD4+ve and FOXP3+ve T cells around αvβ6+ve DCIS ducts compared to αvβ6-ve ducts (P=<0.01), suggesting an increase in Treg cells. In-vivo, Matrigel plugs containing injected into the flanks of female C57/Blk6 normal mice generated influx of higher levels of CD4+ve cells (p=0.005) and FOXP3+ T cells (p=0.007) in the presence of αvβ6+ve myoepithelial cells compared to αvβ6-ve cells, supporting the findings in human tissue samples. Since Treg cells produce TRAIL that can induce apoptosis, we investigated the influence of αvβ6 on myoepithelial cells on the levels of TRAIL in T cells and the hypothesis that αvβ6-positive myoepithelial ells may be more susceptible to TRAIL-induced apoptosis, leading to loss of the myoepithelial barrier. Firstly, levels of TRAIL in Jurkat and primary T cell populations co-cultured with β4 (ii) or β6 myoepithelial cells were measured. This demonstrated a higher level of TRAIL in primary T cells co-cultured β6 myoepithelial cells compared to those co-cultured with β4 myoepithelial cells. β6+ve and β6-ve myoepithelial cells were exposed to TRAIL, and this demonstrated that TRAIL enhanced apoptosis, measured by cleaved PARP, in β6+ve cells. Furthermore, these cells showed loss of the anti-apoptotic protein Galectin-7, and knockdown of Galectin-7 in normal β6-ve myoepithelial cells rendered them more susceptible to TRAIL-induced apoptosis. In DCIS tissues, an inverse relationship between αvβ6 and Galectin-7 in myoepithelial cells was demonstrated, and Cytokine Array analysis showed that αvβ6+ve myoepithelial cells express higher levels of IL-16, which has a role in Treg cell recruitment. Taken together these results suggest that expression of αvβ6 by myoepithelial cells in DCIS generates a tumour-promoter peri-ductal inflammatory infiltrate through altered cytokine release, is associated with reduced galectin-7 expression and enhances myoepithelial cell apoptosis in response to TRAIL. This provides a potential mechanism by which myoepithelial cells may be lost during evolution of DCIS and so contribute to progression to invasive disease.

<p>The incidence of breast cancer is rising steadily in Sweden and the proportion of carcinoma in situ (CIS) has increased appreciably, most likely due to mammography screening. The aim of this study was twofold: (1) to examine risk factors for subsequent invasive breast carcinoma and breast cancer death after primary ductal carcinoma in situ (DCIS) and (2) to study the biology in the progress between in situ and invasive carcinoma.</p><p> In a cohort-study based on 3,398 women with a primary CIS reported to the Swedish Cancer Registry (SCR) 1980-1992, women diagnosed in 1989-1992 ran a relative risk of 0.1 (CI 95%, 0.0-0.9) from dying of breast cancer as compared with women diagnosed in 1980-1982. Women in counties with mammography screening ran a relative risk of 0.2 (CI 95%, 0.0-2.1) for breast cancer death in comparison with women in non-screening counties.</p><p> In a case-control study derived from all 4,661 women with primary CIS reported to the SCR 1960-1992, we investigated risk factors for subsequent invasive breast carcinoma (n=118) and breast cancer death (n=39). Large size and multifocality were found to increase the risk for breast cancer death. Postoperative radiotherapy and mastectomy lowered the risk for ipsilateral invasive cancer.</p><p> The standardised incidence rates (SIR) for invasive breast cancer were estimated in the cohort from 1980-1992. The SIR after primary DCIS and primary lobular carcinoma in situ (LCIS) was 4.5 (CI 95%, 3.7-5.5) and 4.0 (CI 95%, 2.1-7.5), respectively.</p><p> New histopathological classification systems for DCIS were evaluated in 195 women consecutively diagnosed with primary DCIS between 1986-1994. One group with highly differentiated lesions was defined with the EORTC classification system and had an excellent prognosis.</p><p> Histopathological grade and expression of p53, c-erbB-2, Ki 67, hormone receptors, Bcl-2 and angiogenesis were compared in 626 women with either a pure DCIS, a small invasive carcinoma or a lesion with both an invasive and in situ component. When grade was taken into account, no change in tumour markers could be detected that signalled the progression from an in situ stage to invasiveness. All tumour markers correlated to grade and their distribution was very similar in the two components of mixed lesions.</p>

The incidence of breast cancer is rising steadily in Sweden and the proportion of carcinoma in situ (CIS) has increased appreciably, most likely due to mammography screening. The aim of this study was twofold: (1) to examine risk factors for subsequent invasive breast carcinoma and breast cancer death after primary ductal carcinoma in situ (DCIS) and (2) to study the biology in the progress between in situ and invasive carcinoma. In a cohort-study based on 3,398 women with a primary CIS reported to the Swedish Cancer Registry (SCR) 1980-1992, women diagnosed in 1989-1992 ran a relative risk of 0.1 (CI 95%, 0.0-0.9) from dying of breast cancer as compared with women diagnosed in 1980-1982. Women in counties with mammography screening ran a relative risk of 0.2 (CI 95%, 0.0-2.1) for breast cancer death in comparison with women in non-screening counties. In a case-control study derived from all 4,661 women with primary CIS reported to the SCR 1960-1992, we investigated risk factors for subsequent invasive breast carcinoma (n=118) and breast cancer death (n=39). Large size and multifocality were found to increase the risk for breast cancer death. Postoperative radiotherapy and mastectomy lowered the risk for ipsilateral invasive cancer. The standardised incidence rates (SIR) for invasive breast cancer were estimated in the cohort from 1980-1992. The SIR after primary DCIS and primary lobular carcinoma in situ (LCIS) was 4.5 (CI 95%, 3.7-5.5) and 4.0 (CI 95%, 2.1-7.5), respectively. New histopathological classification systems for DCIS were evaluated in 195 women consecutively diagnosed with primary DCIS between 1986-1994. One group with highly differentiated lesions was defined with the EORTC classification system and had an excellent prognosis. Histopathological grade and expression of p53, c-erbB-2, Ki 67, hormone receptors, Bcl-2 and angiogenesis were compared in 626 women with either a pure DCIS, a small invasive carcinoma or a lesion with both an invasive and in situ component. When grade was taken into account, no change in tumour markers could be detected that signalled the progression from an in situ stage to invasiveness. All tumour markers correlated to grade and their distribution was very similar in the two components of mixed lesions.

The Polycomb group (PcG) family of proteins form chromatin-modifying complexes essential for embryonic development, and stem cell renewal and are commonly deregulated in cancer. There are several reports that address the possible implication of PcG proteins in tumor progression and metastasis, but very little is known about the specific role of these proteins in tumor progression and invasion. On the other hand, the molecular processes of the worst cancer prognosis, metastasis, which leads to an incurable disease, are yet incompletely elucidated. Here we show a role for Ring1B, a PcG protein, in three processes related to metastasis: in the Epithelial-mesenchymal transition (EMT), a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors, an in the migration and the invasion of mammary epithelial cells. / Las proteínas del grupo Polycomb (PcG) forman complejos modificadores de la cromatina esenciales en el desarrollo embrionario y en la renovación de las células madre, y su desregulación ha sido asociada al cáncer. Varios estudios muestran la posible implicación de las proteínas de PcG en la progresión tumoral y en la metástasis, pero a pesar de ello se sabe muy poco de los procesos moleculares en los que estas proteínas están participando. Por otro lado, los procesos moleculares responsables del peor pronóstico en cáncer, la metástasis, que continua siendo una enfermedad incurable, siguen sin estar completamente elucidados. En esta disertación mostramos el papel de Ring1B, una proteína del PcG, en tres procesos implicados en la metástasis: en la transición epitelio-mesénquima (EMT), un proceso morfogénico crítico en el desarrollo embrionario y durante la progresión de varios cánceres epiteliales, y en la migración y la invasión de las células epiteliales mamarias.