Abstract 2064: Atm is required for homeostasis within the lactating mammary gland

Abstract

Abstract ATM is a protein kinase activated in response to DNA damage and oxidative stress. Limited evidence suggests that ATM functions in mammary gland development and tumor suppression. However, we now document that mice with germ line loss of Atm exhibit severely blunted mammary gland development. To examine a role for Atm within the mammary gland we generated a novel mouse line with conditional deletion of Atm (AtmWAP-cre) in the mammary epithelium. Characterization of the AtmWAP-cre mouse line indicated that reduced Atm expression results in a progressive lactation defect as judged by a reduction in pup growth rate, aberrant lobulo-alveolar structure, and significantly diminished expression of several milk protein genes in mid-lactation dams. We also document that lactating AtmWAP-cre dams exhibit both morphological and molecular features consistent with premature entry into involution. These aberrant events in Atm-deficient glands occur independently of established Jak/Stat signaling mechanisms that normally control mammary gland development. We found that RNA harvested from lactating Atm-deficient mammary glands contain heightened levels of oxidized guanine (8-oxoGua) indicating unchecked response to oxidative damage. Finally, we knocked down ATM expression in human and mouse mammary epithelium-derived lines and measured increased sensitivity to oxidative stress. This study supplies evidence for a novel biological function for Atm within the mammary gland and provides new insight into the critical importance of oxidative stress response during the high metabolic burden associated with the process of lactation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2064. doi:1538-7445.AM2012-2064