Ethnicity is considered to be one of the major risk factors in certain subtypes of breast cancer. However, the mechanism of this racial disparity remains poorly understood. Here, we demonstrate that SOS1, a key regulator of Ras pathway, is highly expressed in African-American (AA) patients with breast cancer compared with Caucasian-American patients. Because of the higher obesity rate in AA women, increased levels of SOS1 facilitated signal transduction of the c-Met pathway, which was highly activated in AA patients with breast cancer via hepatocyte growth factor secreted from adipocytes. Elevated expression of SOS1 also enhanced cancer stemness through upregulation of PTTG1 and promoted M2 polarization of macrophages by CCL2 in metastatic sites. SOS1 was epigenetically regulated by a super-enhancer identified by H3K27ac in AA patients. Knockout of the super-enhancer by CRISPR in AA cell lines significantly reduced SOS1 expression. Furthermore, SOS1 was posttranscriptionally regulated by miR-483 whose expression is reduced in AA patients through histone trimethylation (H3K27me3) on its promoter. The natural compound, taxifolin, suppressed signaling transduction of SOS1 by blocking the interaction between SOS1 and Grb2, suggesting a potential utility of this compound as a therapeutic agent for AA patients with breast cancer. Significance: These findings elucidate the signaling network of SOS1-mediated metastasis in African-American patients, from the epigenetic upregulation of SOS1 to the identification of taxifolin as a potential therapeutic strategy against SOS1-driven tumor progression.

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Current clinical antidiabetic drugs, like rosiglitazone 1, have been implicated in some serious side effects like edema, weight gain, and heart failure, making it necessary to find alternative agents. Partial agonists of peroxisome-proliferator activated receptor-gamma (PPARγ) were determined to possess improved insulin sensitivity without undeseirable side-effects when compared to full agonists of PPARγ, like rosiglitazone 1. The traditional Chinese medicine (TCM) plants, Goji (Lycium barbarum and Lycium chinense) are widely used for treating symptoms related to various diseases including diabetes and hypertension. Twenty-seven reported compounds from Goji were docked into both partial-and full-agonist binding sites of PPARγ. Amongst the docked compounds, phenylethylamide-based phytochemicals (5-9) (termed as tyramine-derivatives, TDs) were found to possess good docking scores and binding poses with favorable interactions. Synthesis of 24 TDs, including three naturally occuring amides (6, 8, 9) were synthesized and tested for PPARγ gene induction with cell-based assay. Three compounds showed similar or higher fold induction than the positive control, rosiglitazone. Among these three active TDs, trans-N-feruloyloctopamine (9) and tyramine derivatives-enriched extract (TEE) (21%) of the root bark of L. chinense were further studied in vivo using db/db mice. However, both TEE as well as 9 did not show significant antidiabetic properties in db/db mice. In vivo results suggest that the proposed antidiabetic property of Lycium species may not be due to tyramine derivatives alone. Further studies of tyramine derivatives or enriched extract(s) for other bioactivities like hypocholesterolemic activities, and studies of novel isolated compounds from Goji will enable a more complete understanding of their bioactivities.

<div>Abstract<p>Ethnicity is considered to be one of the major risk factors in certain subtypes of breast cancer. However, the mechanism of this racial disparity remains poorly understood. Here, we demonstrate that SOS1, a key regulator of Ras pathway, is highly expressed in African-American (AA) patients with breast cancer compared with Caucasian-American patients. Because of the higher obesity rate in AA women, increased levels of SOS1 facilitated signal transduction of the c-Met pathway, which was highly activated in AA patients with breast cancer via hepatocyte growth factor secreted from adipocytes. Elevated expression of SOS1 also enhanced cancer stemness through upregulation of PTTG1 and promoted M2 polarization of macrophages by CCL2 in metastatic sites. SOS1 was epigenetically regulated by a super-enhancer identified by H3K27ac in AA patients. Knockout of the super-enhancer by CRISPR in AA cell lines significantly reduced SOS1 expression. Furthermore, SOS1 was posttranscriptionally regulated by miR-483 whose expression is reduced in AA patients through histone trimethylation (H3K27me3) on its promoter. The natural compound, taxifolin, suppressed signaling transduction of SOS1 by blocking the interaction between SOS1 and Grb2, suggesting a potential utility of this compound as a therapeutic agent for AA patients with breast cancer.</p>Significance:<p>These findings elucidate the signaling network of SOS1-mediated metastasis in African-American patients, from the epigenetic upregulation of SOS1 to the identification of taxifolin as a potential therapeutic strategy against SOS1-driven tumor progression.</p></div>