HER2 Support Group Forums - how does her2+ breast cancer start? we are getting closer to knowing!!

Oncogene. 2011 Mar 21. [Epub ahead of print]
YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification.
Davies AH, Barrett I, Pambid MR, Hu K, Stratford AL, Freeman S, Berquin IM, Pelech S, Hieter P, Maxwell C, Dunn SE.

Laboratory of Oncogenomic Research, Departments of Pediatrics and Experimental Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

Abstract
Y-box binding protein-1 (YB-1) expression in the mammary gland promotes breast carcinoma that demonstrates a high degree of genomic instability. In the present study, we developed a model of pre-malignancy to characterize the role of this gene during breast cancer initiation and early progression. Antibody microarray technology was used to ascertain global changes in signal transduction following the conditional expression of YB-1 in human mammary epithelial cells (HMEC). Cell cycle-associated proteins were frequently altered with the most dramatic being LIM kinase 1/2 (LIMK1/2). Consequently, the misexpression of LIMK1/2 was associated with cytokinesis failure that acted as a precursor to centrosome amplification. Detailed investigation revealed that YB-1 localized to the centrosome in a phosphorylation-dependent manner, where it complexed with pericentrin and γ-tubulin. This was found to be essential in maintaining the structural integrity and microtubule nucleation capacity of the organelle. Prolonged exposure to YB-1 led to rampant acceleration toward tumorigenesis, with the majority of cells acquiring numerical and structural chromosomal abnormalities. Slippage through the G(1)/S checkpoint due to overexpression of cyclin E promoted continued proliferation of these genomically compromised cells. As malignancy further progressed, we identified a subset of cells harboring HER2 amplification. Our results recognize YB-1 as a cancer susceptibility gene, with the capacity to prime cells for tumorigenesis.Oncogene advance online publication, 21 March 2011; doi:10.1038/onc.2011.82.

PMID: 21423216

Translation--this gene when expressed throws a monkey wrench in the machinery by which breast cells divide --doubling their chromosomes and then splitting them while keeping the chromosomes tethered at a location which buttons the two together, the centrosome. When this gets messed up, the two cells resulting get uneven and extra sets of chromosomes/parts of chromosomes and so have the wrong information in their nucleus. They become hard to stop dividing growing by overexpressing cyclin E (which is like being related to the chief of police and allows the cell to bypass the police stop and keep on going dividing) and results in a subset of cells with too much of an arm of the 17th chromosome --the arm containing the oncogene her2. Since this oncogene confers a survival advantage on those cells with lots of it (like weeds have a survival advantage in a lawn and outcompete the rest of the plants) what results is a tumor with high her2 overexpression (the cells with low expression just could not divide and grow as much sort of like a population of Somalians in an area in Germany ie, with time they will grow to be a large percent of the population because they multiply much faster, more extensively)

If this is indeed the fundamental change causing her2+ bc, it will make it easier to find ways to block its development in the first place and hopefully prevent it!