Abstract
When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.
Highlights
All cells, including tumor cells, exist not in a vacuum but in a continuous, interconnected and unbounded network of relationships
Our own observations are in accordance with those published in similar studies [27,28,29,30] and gives evidence to the selection of epidermal growth factor (EGF) as a trigger for the processes of migration and invasion in MDA-MB-23 cells
We have proven the validity and usefulness of this approach by demonstrating how Annexin A2, one of the elucidated proteins, plays a pivotal role in maintaining the malignant phenotype of estrogen receptor negative breast cancer
Summary
All cells, including tumor cells, exist not in a vacuum but in a continuous, interconnected and unbounded network of relationships. Invasion, referred to as the defining feature of malignancy, is the ability of cancer cells to change their morphology and alter their surroundings in order to penetrate the basement membrane, degrade encompassing stroma and escape usual tissue boundaries [5]. These pivotal mechanisms of cancer disease progression can be modelled in vitro using cell lines and well-defined transwell migration and invasion assays [6]
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