Pathogenic BRCA1 Variants Disrupt PLK1-Regulation of Mitotic Spindle Orientation
This week we profile a recent publication in Nature Communications from first author Dr. Leo (Zhengcheng) He
(pictured, left) in the lab of Dr. Chris Maxwell (right) at BC Children’s Hospital and UBC.
Can you provide a brief overview of your lab’s current research focus?
My lab studies how cells grow and move in tissues and tumors to better understand that molecules and pathways that underlie hereditary and childhood cancers. We want to understand the cellular functions normally supported by genes that are frequently mutated in hereditary and childhood cancers. These discoveries will enable us to detect their disruption early and to develop treatments that capitalize on the sensitivities of hereditary cancer cells.
What is the significance of the findings in this publication?
Women that are born with a pathogenic BRCA1 mutation are at an elevated risk to develop breast cancer in their lifetime. The results reported in this study provide two important and entirely new insights into the mechanisms by which pathogenic variants of BRCA1 alter normal mammary cell biology. The present study now discovers that reduced activity of pathogenic BRCA1 mutant proteins (also simulated by simply reducing normal BRCA1 levels) specifically disrupts both the positioning of the mitotic spindle and the ability of the daughter cells to acquire features of mature luminal cells. We also show that this consequence of reduced BRCA1 activity is replicated in Brca1-/- mouse mammary cells indicating its evolutionary conservation. Moreover, these properties are dependent on elevated activity of a mitotic kinase and are reversible through the treatment of mutant cells with a very low dose of a mitotic kinase small-molecule inhibitor. Together, these data may mechanistically explain the premalignant phenotypic changes in the breast, and the type of tumors later produced, identified in the female BRCA1 mutation carriers.
What are the next steps for this research?
We are very interested in understanding how the loss of this pathway may affect hormone-regulated growth and development of human breast epithelial cells. The loss of the ability to correctly orient the cell division axis in mammary epithelial cells isolated from female BRCA1 mutation carriers is likely to affect the normal differentiation process, as has been directly observed in Brca1-/- mice and has been suggested through retrospective analysis of carrier’s tissues. If so, this disrupted pathway is likely to provide biomarkers that predict for future tumorigenesis of the breast. Moreover, hyperactive molecules that disrupt this pathway may be corrected through targeted inhibition and provide new treatment options for BRCA1-associated breast cancers.
If you’d like to mention your funding sources, please list them.
This study was partially funded by grants from the Canadian Institutes of Health Research, the Canadian Cancer Research Institute, the Canadian Cancer Society, the Michael Cuccione Foundation for Childhood Cancer Research, and the BC Children’s Hospital Research Institute. The lead author received University of British Columbia Four Year Doctoral Fellowships. We would also like to acknowledge the data provided by BCAC and CIMBA consortia and the discussions and assistance provided by Dr. John Stingl.