Publicação
The role of rab11a and rab11b in breast cancer progression
| Resumo: | Breast cancer is the most frequent type of cancer worldwide and the leading cause of cancer-related deaths in women. Although the mortality from breast cancer in developed countries has declined in recent years, due to early detection and advances in adjuvant therapy, metastasis remains by far the main cause of mortality in breast cancer patients. Therefore, the development of therapies to impair metastasis and the identification of biomarkers that predict breast cancer progression is essential to reduce patient mortality. This goal requires an understanding of the molecular mechanisms that regulate not only the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) but also subsequent cancer cell invasion. To be able to invade and form metastases, cancer cells subvert a wide range of cellular processes that enable them to adapt and overcome the micro-environmental barriers. Accumulating evidence suggests that membrane traffic is subverted by cancer cells to increase their proliferative, migratory and invasive capacities. Rab GTPases are key regulators of all steps of membrane traffic and were found to be dysregulated in several types of cancer and implicated in various aspects of tumor progression. Among the different Rabs, RAB11 subfamily has been shown to regulate vesicular trafficking by mediating transport of cargo from the endocytic recycling compartment to the trans-Golgi network and to the plasma membrane through recycling pathways. Interestingly, RAB11 isoforms (RAB11A, RAB11B and RAB25) have been associated with multiple biological processes of malignant tumors and poor prognosis. RAB25 is the most studied isoform in breast cancer, in which it has been shown to act as a tumor promoter or tumor suppressor depending on the molecular context. However, in contrast to the functions of RAB25, the role of RAB11A and RAB11B in breast cancer progression is still poorly understood. Therefore, the main objective of this PhD thesis was to determine the role of RAB11A and RAB11B in breast carcinogenesis and identify the underlying molecular mechanisms driving breast cancer progression. The results obtained in this work show that RAB11A mRNA levels are increased in breast cancer patient samples, comparing with paired adjacent tissues. Moreover, increased levels of RAB11A and RAB11B are positively correlated with the invasive capacity of different breast cancer cell lines. We observed that overexpression of RAB11 isoforms does not promote invasion in an in situ breast cancer spheroid model. Nevertheless, RAB11A enhances the proliferation of in situ breast cancer cells, suggesting that this isoform plays an important role during the early stages of breast cancer formation. Even though RAB11A and RAB11B do not mediate the transition from DCIS to IDC, we show that downregulation of each isoform inhibits proliferation as well as single and collective migration in a highly invasive triple-negative breast cancer cell line. In addition, RAB11A and RAB11B silencing impairs invasion in a breast cancer spheroid model of this cell line. Notably, RAB11 isoforms were shown to regulate the formation and activity of invadopodia, which are structures involved in the proteolytic degradation of the extracellular matrix. Interestingly, RAB11A and RAB11B regulate epithelial-mesenchymal transition by modulating the mRNA levels of SNAIL and SLUG. Finally, we also observed a decrease in the activation of the PI3K/AKT signaling pathway, upon downregulation of each isoform. It has been shown that invadopodia are necessary for cancer cell intravasation and extravasation during the metastatic cascade. Therefore, targeting the mechanisms that promote invadopodia formation and activity is regarded as a promising strategy to impair the development of metastases at any stage. Thus, we propose RAB11A and RAB11B as potential therapeutic targets to impair the formation of metastases. |
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| Autores principais: | Castanheira, Pedro |
| Assunto: | RAB11A RAB11B Breast Cancer |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Breast cancer is the most frequent type of cancer worldwide and the leading cause of cancer-related deaths in women. Although the mortality from breast cancer in developed countries has declined in recent years, due to early detection and advances in adjuvant therapy, metastasis remains by far the main cause of mortality in breast cancer patients. Therefore, the development of therapies to impair metastasis and the identification of biomarkers that predict breast cancer progression is essential to reduce patient mortality. This goal requires an understanding of the molecular mechanisms that regulate not only the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) but also subsequent cancer cell invasion. To be able to invade and form metastases, cancer cells subvert a wide range of cellular processes that enable them to adapt and overcome the micro-environmental barriers. Accumulating evidence suggests that membrane traffic is subverted by cancer cells to increase their proliferative, migratory and invasive capacities. Rab GTPases are key regulators of all steps of membrane traffic and were found to be dysregulated in several types of cancer and implicated in various aspects of tumor progression. Among the different Rabs, RAB11 subfamily has been shown to regulate vesicular trafficking by mediating transport of cargo from the endocytic recycling compartment to the trans-Golgi network and to the plasma membrane through recycling pathways. Interestingly, RAB11 isoforms (RAB11A, RAB11B and RAB25) have been associated with multiple biological processes of malignant tumors and poor prognosis. RAB25 is the most studied isoform in breast cancer, in which it has been shown to act as a tumor promoter or tumor suppressor depending on the molecular context. However, in contrast to the functions of RAB25, the role of RAB11A and RAB11B in breast cancer progression is still poorly understood. Therefore, the main objective of this PhD thesis was to determine the role of RAB11A and RAB11B in breast carcinogenesis and identify the underlying molecular mechanisms driving breast cancer progression. The results obtained in this work show that RAB11A mRNA levels are increased in breast cancer patient samples, comparing with paired adjacent tissues. Moreover, increased levels of RAB11A and RAB11B are positively correlated with the invasive capacity of different breast cancer cell lines. We observed that overexpression of RAB11 isoforms does not promote invasion in an in situ breast cancer spheroid model. Nevertheless, RAB11A enhances the proliferation of in situ breast cancer cells, suggesting that this isoform plays an important role during the early stages of breast cancer formation. Even though RAB11A and RAB11B do not mediate the transition from DCIS to IDC, we show that downregulation of each isoform inhibits proliferation as well as single and collective migration in a highly invasive triple-negative breast cancer cell line. In addition, RAB11A and RAB11B silencing impairs invasion in a breast cancer spheroid model of this cell line. Notably, RAB11 isoforms were shown to regulate the formation and activity of invadopodia, which are structures involved in the proteolytic degradation of the extracellular matrix. Interestingly, RAB11A and RAB11B regulate epithelial-mesenchymal transition by modulating the mRNA levels of SNAIL and SLUG. Finally, we also observed a decrease in the activation of the PI3K/AKT signaling pathway, upon downregulation of each isoform. It has been shown that invadopodia are necessary for cancer cell intravasation and extravasation during the metastatic cascade. Therefore, targeting the mechanisms that promote invadopodia formation and activity is regarded as a promising strategy to impair the development of metastases at any stage. Thus, we propose RAB11A and RAB11B as potential therapeutic targets to impair the formation of metastases. |
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