Targeting HP1 regulated pathways to suppress breast cell invasion

Project Objective
Metastasis is the primary cause of death in breast cancer patients as it refractory to current therapies. The first step in metastatic disease occurs when a cell invades surrounding tissue. However, before a cell can invade, its nucleus must become malleable enough to ensure the cell can squeeze through the local tissue matrix. The requirement for nuclear reorganization at this critical stage provides a unique opportunity to prevent metastasis by targeting the key pathways involved.

Heterochromatin Protein 1a (HP1a) maintains the highly-condensed portion of the genome and tethers it to the nuclear membrane. We propose the loss of HP1a that is commonly observed in invasive breast tumours, is responsible for the changes in nuclear architecture that lead to increased nuclear malleability in these cells. Therefore, by exploring nuclear remodelling pathways regulated by HP1a, we will reveal potential new drug targets for therapy of metastatic breast disease.

Understanding the changes that occur to allow a cancer cell to invade surrounding tissue is vital as this is the first step towards metastatic breast cancer. This research has shown that reduction of a protein, HP1α, that helps compact the DNA within the cell's nucleus promotes this step in a cancer cell. The loss of HP1α reduces the compaction of the DNA and also alters the nuclear lamina that surrounds the DNA. By testing the mechanical properties of the nucleus we have shown that these alterations lead to an increase in the malleability of the nucleus. This promotes the invasive potential of malignant cells, as they need to squeeze through surrounding cells and can only do so when their nucleus is less rigid. The changes that lead to reduced DNA compaction and lamina dysfunction identified in this study represent potential targets to intervene in the metastatic process thus preventing the spread of tumour cells. 

HOST INVESTIGATOR: Massey University