Retinoic acid and estrogen signaling pathways in tamoxifen resistant breast cancer cells

Resum

The majority of breast tumors (70-75%) express estrogen receptor alpha (ER¿) protein, which impliesthat the ER signaling pathway is a major target for therapy. Tamoxifen, an ER antagonist, is one of themost commonly used treatments for women with ER-positive breast cancer. Unfortunately, many patientswill present intrinsic resistance or develop acquired resistance to treatment. The mechanisms of endocrineresistance are still not fully comprehended.A large body of research has identified stem cells in normal tissues. In addition, studies of neoplastictissues have provided evidence of self-renewing, stem-like cells within tumors, which have been calledcancer stem cells (CSCs). CSCs constitute a small percentage of neoplastic cells within a tumor and aredefined functionally by their ability to seed new tumors.The main aim of my thesis was to study the development of resistance to treatments such as tamoxifen,chemo- and radiation-therapy and the potential role of breast cancer stem cells (CSCs) in this process. Tostudy the mechanisms of tamoxifen resistance, we used as a model MCF7TamR cells, which were derivedfrom the human ER-positive breast cancer cell line MCF7 by their capacity to resist to tamoxifentreatment. We analyzed ER expression and transcriptional activity in these cells. Furthermore, weperformed proteomic analysis that compared the CSC enriched population from tamoxifen resistant cellswith the CSC population from the parental cells, sensitive to tamoxifen. We identified cellular retinoicacid binding protein 2 (CRABP2) as a potential prognostic factor. In fact, we observed that the retinoicacid (RA) pathway was up-regulated in tamoxifen resistant cells. In conclusion, these findings suggestthat RA could be a potential drug to treat tamoxifen resistant tumors.