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| Author(s): |
Lourival Antunes de Oliveira Filho
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2017-05-11 |
| Examining board members: |
Maria Aparecida Nagai;
Dirce Maria Carraro;
Maria Lucia Zaidan Dagli;
Maria Aparecida Azevedo Koike Folgueira
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| Advisor: | Maria Aparecida Nagai |
| Abstract | |
Breast cancer is the most incident tumor and the leading cause of mortality among women worldwide. Like other forms of cancer, breast cancer has a complex, heterogeneous and multifactorial etiology. The pro-apoptotic gene PAWR (PKC apoptosis WT1 regulator; also known as PAR-4, Prostate Apoptosis Response-4) is known to selectively induce apoptosis in a wide variety of cancer cells. The role of Par- 4 as a tumor suppressor has been well established in recent years. However, little has been explored about the role and mechanisms of Par-4 suppressor function in breast cancer. Previous work from our research group demonstrated that the reduced expression of Par-4 is associated with a worse prognosis in breast cancer. Also an important role of Par-4 in the morphogenesis of the mammary gland was suggested. In addition, Par-4 overexpression in MCF-7 cells increased the sensitivity to docetaxel treatment. In order to better understand the role of Par-4 in breast tumor cells, we investigated the effect of Par-4 knock-down on MDA-MB-231 cells in vitro and in vivo. We performed shRNA-mediated Par-4 knockdown, and then carried out functional assays. The reduced expression of Par-4 was able to increase the colony formation capacity of MDA-MB-231 cells in culture. In addition, shRNA-Par-4 transfection in MDA-MB-231 cells led to a significant reduction of cell death (sub-G0/G1 cell cycle), particularly by apoptosis (Annexin-FITC/PI), after treatment with different chemotherapeutic agents. In our study, docetaxel-treated MDA-MB-231-Control cells showed increased levels of secreted Par-4, which was not observed in MDA-MB-231- shPar-4 cells. Finally, our in vivo results suggest that diminished Par-4 expression may modulate tumor growth in Balb/c NUDE mice. Taken together, our data support the suppressor role of Par-4 already described in the literature and confirm its suppressive action in different breast cancer cell lines (AU) | |
| FAPESP's process: | 13/08110-0 - Role of cellular and extra-cellular PAR-4 expression in tumor formation and drug sensitivity |
| Grantee: | Lourival Antunes de Oliveira Filho |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |