PhD Proposal Exam – Luís Eduardo Abatti – Thursday, January 25th , 2018

PhD Proposal Exam

Tuesday, January 25^th, 2018 at 10:10 am – Ramsay Wright Building, Room 432

Luís Eduardo Abatti  (Mitchell lab)

“Investigating the SOX2 transcriptional network in estrogen-responsive and estrogen-resistant breast cancer cells”

Abstract

Breast cancer is a multifactorial disease characterized by aberrant gene expression. The sex-determining region Y box2 (SOX2), a key transcription factor associated with pluripotency, is often overexpressed in breast cancer cells, where it has been linked to epithelial-mesenchymal transition (EMT) and hormone resistance. In mouse embryonic stem cells, Sox2 is regulated by a wide transcription factor network that interacts with its distal enhancer. However, the SOX2 transcriptional network in breast cancer cells remains unknown. Mammary epithelial cells rely on the estrogen receptor alpha (ESR1) and its cofactors – FOXA1 and GATA3 – to properly respond to estrogen stimulation, while breast cancer cells frequently display a dysfunctional estrogen response. My hypothesis is that SOX2 is normally downregulated by the repressive action of ESR1, FOXA1 and GATA3 at a distal enhancer. Once the estrogen pathway is disrupted in hormone-resistant cells, the repressive effect of estrogen over SOX2 expression is abolished, and SOX2 recruits the RNA Polymerase II transcriptional complex at multiple genomic targets. To better understand the role and regulation of SOX2 in this scenario, I propose three objectives: first, to identify the SOX2 transcriptional network in breast cancer cells; second, to investigate SOX2 cis- and trans-regulatory elements in MCF-7 cells; and third, to understand SOX2 upregulation in hormone-resistant MCF-7 cells. This SOX2 functional investigation will elucidate how breast cancer cells rely on this transcription factor to maintain their tumourigenesis and how its upregulation is linked to hormone resistance.