Impact of RANK overexpression on mammary stem cell fate, alveolar cell differentiation and tumorigenesis
[eng] Breast cancer is the second most common cancer worldwide, the fifth most common cause of cancer death, and the leading cause of cancer death in women. Distinct biological features and clinical behaviors turn cancer into a very heterogeneous disease, and although significant advances in the fig...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2015 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/102752 |
| Acceso en línea: | https://hdl.handle.net/2445/102752 http://hdl.handle.net/10803/396176 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer de mama Breast cancer Cèl·lules mare Stem cells |
| Sumario: | [eng] Breast cancer is the second most common cancer worldwide, the fifth most common cause of cancer death, and the leading cause of cancer death in women. Distinct biological features and clinical behaviors turn cancer into a very heterogeneous disease, and although significant advances in the fight against breast cancer have been achieved during the last decades, a more profound understanding of their biology is still needed. This thesis project is focused in RANK/RANKL signaling pathway, as during the last decade it has emerged as a key pathway in mammary gland development and tumorigenesis. RANK deletion or overexpression under the MMTV promoter disrupts mammary gland differentiation during pregnancy and lactation (Fata et al. 2000; Gonzalez-Suarez et al. 2007). It has been demonstrated that RANKL is downstream of progesterone and mediates its proliferative effects in the mammary gland (Beleut et al. 2010). Moreover, pharmacological inhibition of RANKL signaling prevents mammary tumor formation in WT mice under a carcinogenic treatment that includes a mutagen (dimethylbenz(a)anthracene, DMBA) and an analogous of progesterone (medroxiprogesterone, MPA) (Gonzalez-Suarez et al. 2010). First, we aimed to elucidate how RANK signaling is regulating mammary gland differentiation. We demonstrated that RANK regulates different populations in mammary epithelial hierarchy. Indeed, constitutive activation of RANK in the mammary gland not only expands mammary stem cells (MaSC) and intermediate progenitors, but also reduced alveolar progenitors and impairs its differentiation into alveolar milk-producing cells through downregulation of the PrlR/STAT5/Elf5 signaling pathway. In addition we demonstrated that NF-KB, a signaling pathway activated downstream of RANK, regulates the balance between MEC self-renewal and differentiation. Reproductive story and age have been linked to mammary tumorigenesis, and we found that increased levels of RANK in the mammary gland promote spontaneous tumor formation in mice under multiple gestations. We have also addressed the impact of RANK overexpression in two mouse models of spontaneous and metastatic hormone receptor negative breast cancer: MMTV-NEU and MMTV-PYMT. We demonstrated that RANK signaling plays a complex role in mammary tumorigenesis, affecting tumor initiation and/or aggressiveness in those oncogene-driven mouse models. As we discovered that RANK signaling regulates mammary stem cell fate, we investigated whether this signaling pathway plays a role in the regulation of the cancer stem cell population. We demonstrated that RANK overexpression expands the cancer stem cell pool in PYMT-driven tumors, whereas RANK signaling blockage with RANK-Fc not only reduced this cancer stem cell population, but also induced tumor cell differentiation, resulting in decreased tumor recurrence and metastasis. Genetic deletion of RANK in MMTV-PYMT mice confirmed that RANK is important in tumor formation and mediates the metastatic potential of mammary tumor cells. Altogether, our results supported that blocking RANKL could be a novel therapeutic therapy to treat both human hormone receptor positive and negative breast tumor subtypes. |
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