Targeting Chromosomal Instability in Breast Cancer
Chromosomal instability—the gain or loss of whole chromosomes—is a hallmark of aggressive breast cancers and is linked to treatment resistance and poor patient outcomes. Despite decades of research, the enzymes and regulatory complexes that drive this instability remain incompletely understood as therapeutic targets. Our lab was the first to identify Separase, the protease that resolves sister chromatid cohesion, as an oncogene. We are now translating that discovery into a new class of targeted inhibitors to treat refractory breast cancers.
Our Discoveries
Our lab has made foundational contributions to understanding how chromosomal cohesion and separation drive cancer. The following discoveries are laying the foundation for the development of targeted therapies:
Separase is an oncogene that drives aneuploidy and tumorigenesis
Aberrant overexpression of Separase induces chromosomal missegregation, aneuploidy, and mammary tumorigenesis, establishing Separase as a bona fide oncogene.
Separase is overexpressed and mislocalized in multiple human cancers
The constitutive nuclear localization and overexpression of Separase correlates with aggressive disease, relapse, and reduced survival across multiple human cancers.
Identification and characterization of Separase inhibitors for cancer therapy
Small-molecule inhibitors suppress oncogenic signaling and tumor cell growth, demonstrating that Separase is a druggable therapeutic target.
A "Handcuff" model for how cohesin holds sister chromatids together
Two cohesin rings — not one — embrace sister chromatids in a handcuff-like configuration, and a calpain-1 pathway provides a Separase-independent route for cohesin cleavage.
Watch this short animation, which highlights our exciting discovery that medulloblastoma cancer cells can spread through the blood, driven by the protein CCL2.
Help us change the future of treatment-resistant breast cancer.
