Identification of the YES1 Kinase as a Therapeutic Target in Basal-Like Breast Cancers

Abstract

Normal cellular behavior can be described as a complex, regulated network of interaction between genes and proteins. Targeted cancer therapies aim to neutralize specific proteins that are necessary for the cancer cell to remain viable in vivo. Ideally, the proteins targeted should be such that their downregulation has a major impact on the survival/fitness of the tumor cells and, at the same time, has a smaller effect on normal cells. It is difficult to use standard analysis methods on gene or protein expression levels to identify these targets because the level thresholds for tumorigenic behavior are different for different genes/proteins. We have developed a novel methodology to identify therapeutic targets by using a new paradigm called "gene centrality." The main idea is that, in addition to being overexpressed, good therapeutic targets should have a high degree of connectivity in the tumor network because one expects that suppression of its expression would affect many other genes. We propose a mathematical quantity called "centrality," which measures the degree of connectivity of genes in a network in which each edge is weighted by the expression level of the target gene. Using our method, we found that several SRC proto-oncogenes LYN, YES1, HCK, FYN, and LCK have high centrality in identifiable subsets of basal-like and HER2+ breast cancers. To experimentally validate the clinical value of this finding, we evaluated the effect of YES1 knockdown in basal-like breast cancer cell lines that overexpress this gene. We found that YES1 downregulation has a significant effect on the survival of these cell lines. Our results identify YES1 as a target for therapeutics in a subset of basal-like breast cancers.

microRNA-125a-3p reduces cells proliferation and migration by targeting Fyn

“…To assess the feasibility of the use of miR-125a-3p as a regulator of Fyn expression in various cancerous cells, we examined the expression of Fyn mRNA in miR-125a-3p-overexpressing cancer cell lines: MNT-1 (melanoma cancer), U2OS (osteosarcoma), MDA-MB-231, MCF-7 and SKBR3 (breast cancers), PC3 (prostate cancer) and HeLa (cervical cancer). The role of Fyn in tumor progression or its overexpression has already been illustrated in these cancer cell lines, with the exception of osteosarcoma (Teutschbein et al, 2009;Huang et al, 2003;Zhao et al, 2011;Posadas et al, 2009;Bilal et al, 2010;Yadav and Denning, 2011). We found that the expression of Fyn mRNA was reduced in all the examined cell lines, except HeLa cells (Fig.…”

PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression

“…Three of the regions were small, containing just one gene: chr17 - RAB11FIP4; chr20 - MACROD2, overexpression of this gene has been implicated in oestrogen-independent growth [27]; and chrX - KLF8, oncogenic in ovarian but not breast cancer cell lines [28]. There was also a similar region on chr18, that was more common in both pure and inv-cLCIS compared to ILC, containing YES1, a SRC proto-oncogene that has recently been identified as a possible therapeutic target in basal breast cancer [29]. It is possible that these regions contain genes that hinder development of the invasive phenotype.…”

Identification of potent Yes1 kinase inhibitors using a library screening approach

“…A recent study examining the downregulation of Yes1 by shRNA found significant effects on cell survival and growth for basal-like and Her2-positive breast cancers. 10 In a similar manner, the knock down of Yes1 expression with shRNA in both embryonal and alveolar rhabdomyosarcoma cell lines (RD and RH30) was found to significantly inhibit cell growth in vitro , thereby implicating Yes1 as a potential therapeutic target for this aggressive cancer. 11 Despite the potential for Yes1 to be a target for the above-described cancers, there are very few reports on the identification of potent and selective inhibitors of Yes1 kinase.…”