Identification and functional analysis of molecular mechanisms involved in the latency of er positive breast cancer

Resumen

Breast cancer is the most frequently diagnosed cancer and remains the second leading cause of death among women in Europe and United States. In this malignancy, metastasis remains to be an incurable condition, and therefore the major cause of death. Metastatic lesions can appear within a wide time ranging from months to years or decades after primary tumor resection. In particular, in the estrogen receptor (ER) positive breast cancer subgroup metastatic latency continues to be a major challenge for the researchers, clinicians and patients. This thesis reports the identification and functional analysis of molecular mechanisms involved in the latency of ER positive breast cancer. For that purpose we based our research on a comprehensive approach that relies on genetically engineered human breast cancer cells, experimental mouse models, unbiased whole-genome screen and clinical data. The first part of the thesis describes a novel mouse model of breast cancer dormancy. We showed that metastatic cells home the bone and enter the latency phase as micrometastatic lesions where tumor growth is restricted mainly due to the equilibrated ratios of cell proliferation and cell death. This experimental mouse model was used to identify genes relevant for long-latent relapse. To this end, we performed in vivo loss-of-function shRNA screening. In the screening we challenged a whole-genome library of shRNA to uncover genes whose depletion negatively regulates dormancy. Among the candidate genes revealed by the screen we focused on MSK1 as a long-latent metastasis regulator. The in vivo and in vitro validation results indicate that MSK1 plays a role in homing and differentiation of metastatic cells. We showed that MSK1 promotes the expression luminal transcription factors - FOXA1 and GATA-3. Therefore, MSK1 depletion is beneficial for metastatic cells leading to a partial phenotype shift towards a more aggressive and poorly differentiated basal population. Furthermore, our data suggest that MSK1 may be involved in metastatic cell plasticity by remodeling the chromatin. Importantly, low MSK1 gene expression levels associate with early metastasis in ER positive breast cancer.