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Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2 high p-p38 low p-MK2 low p-Hsp27 low , which also exist in human breast carcinoma tissues. Suppression of p38 and MK2 by Her2 reduces MK2-mediated Hsp27 phosphorylation, and unphosphorylated Hsp27 binds to β-catenin and enhances its phosphorylation by Src, leading to β-catenin activation and disseminating phenotypes in early lesion breast cancer cells. Pharmacological inhibition of MK2 promotes, while inhibition of a p38 phosphatase Wip1 suppresses, early dissemination in vivo. These findings identify Her2-mediated suppression of the p38-MK2-Hsp27 pathway as a novel mechanism for cancer early dissemination, and provide a basis for new therapies targeting early metastatic dissemination in Her2 + breast cancer.

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.

The phytohormone abscisic acid (ABA) plays a crucial role in mediating plant growth and development by recruiting genetically redundant ABA receptors. To overcome its oxidation inactivation, we developed a novel ABA analog named 2',3'-benzo-iso-ABA (iso-PhABA) and studied its function and structural characterization with A. thaliana ABA receptors. The (+)-iso-PhABA form showed much higher ABA-like activities than (+)-ABA including inhibitory effects on the seed germination of lettuce and A. thaliana, wheat embryo germination and rice seedling elongation. The PP2C (protein phosphatases 2C) activity assay showed that (+)-iso-PhABA acted as a potent and selective ABA receptor agonist, which is preferred to PYL10. In some cases, (-)-iso-PhABA showed moderate to high activity for the PYL protein inhibiting PP2C activity, suggesting different mechanisms of action of iso-PhABA and ABA. The complex crystal structure of iso-PhABA with PYL10 was determined and elucidated successfully, revealing that (+)-iso-PhABA was better coordinated in the same binding pocket compared to (+)-ABA. Moreover, the detailed interaction network of iso-PhABA/PYL10 was disclosed and involves hydrogen bonds and multiple hydrophobic interactions that provide a robust framework for the design of novel ABA receptor agonists/antagonists.