SUMMARY Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2+ cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, Lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically, in concert with a cascade of MLL2-associating epigenetic regulators, to dampen sensitivity of the cancer cells to Lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with Lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy.

Abstract-High salt intake produces vascular changes that contribute to the development of hypertension in salt-sensitive individuals. Because reactive oxygen species play a role in the pathogenesis of cardiovascular diseases, we investigated whether oxidative stress contributes to salt-sensitive hypertension. Sprague-Dawley rats were divided in different groups and received tap water (vehicle), 30 mmol/L of L-buthionine sulfoximine ([BSO] an oxidant), high salt ([HS] 1% NaCl), and BSO plus HS without and with antioxidant tempol (1 mmol/L) in drinking water for 12 days. Compared with vehicle, BSO treatment caused oxidative stress and mild increase in blood pressure. Thoracic aortic rings from BSO-treated rats exhibited decreased response to endothelium-independent vasorelaxants. In HS-treated rats, the response to vasoactive agents, as well as blood pressure, was unaffected. Concomitant treatment of rats with BSO and HS produced a marked increase in blood pressure and a decreased response to both endothelium-dependent and endothelium-independent vasorelaxants with an increase in EC 50 . Incubation of aortic tissue from BSO-treated rats with sodium nitroprusside showed decreased cGMP accumulation, whereas HS rats had decreased basal NO synthase activity. Tempol decreased oxidative stress, normalized blood pressure, and restored NO signaling and responses to vasoactive compounds in BSO and BSO plus HS rats. We conclude that BSO increases oxidative stress and reduces NO signaling, whereas HS reduces NO levels by decreasing the NO synthase activity. These phenomena collectively result in reduced responsiveness to both endothelium -dependent and endothelium-independent vasorelaxants and may contribute to salt-sensitive hypertension. Key Words: acetylcholine Ⅲ hypertension Ⅲ oxidative stress Ⅲ salt sensitivity Ⅲ tempol E ndothelial cells modulate the reactivity of the underlying vascular smooth muscle cells by releasing endotheliumderived relaxing factors. 1,2 Previous studies have demonstrated that elevated dietary salt intake leads to an impaired relaxation of blood vessels to endothelium-dependent relaxations induced by a variety of vasodilator agents. 3-9 A possible contributor to impaired vascular relaxation to dilator stimuli in animals on a high-salt diet is an impaired function of the endothelium. 3-9 Impaired endothelium-dependent dilation in vessels of animals on a high-salt diet could occur either because the acetylcholine (Ach)-mediated production of NO by the endothelium is impaired or because of the failure of NO to cause vasodilation. [3][4][5][6][7][8][9] NO is a major regulator of vascular tone in humans. 10 Decreased production or bioavailability, or decreased vascular response to NO, has been implicated in the pathogenesis of human hypertension. 11,12 An increase in blood pressure (BP) in response to dietary sodium (salt sensitivity) is a well-documented phenomenon in humans and is considered to be an important factor in the pathogenesis of hypertension. 4 In animal models of salt-sensitive hypertens...

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