Abstract P5-06-15: JNK2 Regulates Mammary Epithelial Cell Differentiation Through Inhibition of p53 and Notch-1 Expression

The classification of patient tumors by clinical subtype has gained great interest due to the implications for prognosis and treatment. For example, it is known that the five-year survival rate of patients diagnosed with the basal subtype of breast cancer is considerably lower than those with luminal subtypes because they lack expression of common drug targets. For this reason, it is important to elucidate the molecular mechanisms responsible for differentiation of mammary stem cell populations into basal and luminal cell lineages. Data presented in this poster outline a novel pathway whereby a ubiquitously expressed protein kinase, JNK2, influences the differentiation of basal, myoepithelial cells (MEps) while suppressing luminal cell (LEp) populations. Gross anatomical observation of whole-mounted mammary glands from wildtype (jnk2wt) and jnk2-/- (jnk2ko) mice revealed that JNK2 increases the rate of pubertal development. Loss of jnk2 increased the rate of ductal invasion, branching, and terminal end bud (TEB) count. Although a slight increase in proliferation was seen in jnk2ko glands, data suggested that it was not due to growth factor signaling. Instead, it was noticed that jnk2ko glands possess 35% fewer MEps (p=0.0078) with a corresponding increase in LEp populations (p=0.100). LEps are known to proliferate at a higher rate than MEps. The differentiation phenotype was corroborated through 3D culture of primarymammary epithelial cells (MECs). The rate of growth of 3D MEC acini was 31.5% higher in jnk2ko cultures than in jnk2wt (P notch-1 transcript in vivo (P notch-1 wildtype promoter to a notch-1 promoter with mutated p53 response elements revealed a dependence of increased notch-1 promoter activity in jnk2ko cells on the p53 response element. QPCR showed 2.78 times more p53 transcript in jnk2ko mammary glands as compared to jnk2wt. These data suggest that JNK2 regulates MEC differentiation through p53 and its target, Notch-1. These findings are significant because they reveal JNK2 as a possible drug target for novel differentiation therapy of basal type breast tumors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-15.