Abstract B76: High glucose induces breast cancer progression through upregulating PP2Cδ

Abstract

Breast cancer has a high incidence worldwide. African-American and Hispanic/Latina women have higher mortality from breast cancer than other ethnic groups. Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer. Diabetes and cancer share many risk factors, but the pathophysiologic relationship between the two diseases is incompletely understood in detail. We observed that exposure of cultured transformed (MCF-7) and normal (MCF-12A) breast epithelial cells to clinically relevant levels of glucose (HG, 22 mM) dramatically suppresses the tumor suppressor p53 acetylation, and, consequently, additively promotes tumor cell proliferation, migration, and invasion. Importantly, we found that activation of nuclear phosphatase PP2Cδ (Ppm1d, WIP1) plays a role in the enhancing effects of HG on aggressive phenotypes of these cells. The mechanisms underlying high-glucose stimulation of PP2Cδ involve classical/novel PKCs activation and its downstream target protein GSK3β phosphorylation and inactivation. In addition, HG-induced reactive oxygen species (ROS) generation and subsequent NF-κB activation play a partial role in HG induction of PP2Cδ. HG inhibition of p53 activity and DNA damage-induced apoptosis, as well as induction of cancer cell proliferation, migration, and invasion, were significantly blocked by CCT007093, a known PP2Cδ inhibitor. We conclude that hyperglycemia, via PKC/GSK3β and ROS/NF-κB pathways that are involved in PP2Cδ activation, suppresses the tumor suppressor p53 function and inhibits DNA damage-induced apoptosis, inducing proliferation in the epithelium and the development of breast cancer. Citation Format: Ke Wu, Xiaoting Yu, Xianghua Yi, Lynn Ma, Yahya Elshimali, Yanjun Liu, Donghui Zhu, Yong Wu, Jaydutt V. Vadgama. High glucose induces breast cancer progression through upregulating PP2Cδ [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B76.