Abstract 3777: Autophagy and HER2 interaction in mammary tumorigenesis
Authors: Lozy Fred J. , Reddy Anupama , Miles Gregory , Bhanot Gyan , Ganesan Shridar , Karantza Vassiliki 
Published: June 2012

Abstract
Autophagy is an evolutionarily conserved process involving protein degradation and organelle recycling, which is essential for cellular homeostasis. Faulty autophagy is linked to tumorigenesis, as Beclin 1 (BECN1), an essential autophagy regulator, is monoallelically deleted in human breast, ovarian, and prostate cancers. Ectopic BECN1 expression in MCF7 breast cancer cells inhibits tumor formation, whereas Becn1+/- mice are tumor-prone. Thus, autophagy functions as a tumor suppressor. Cancer cells with deficient autophagy are more susceptible to metabolic stress and accumulate greater DNA damage and higher genomic instability, providing at least one explanation for their increased tumorigenicity. An example of genomic instability in autophagy-deficient mammary cells is gene amplification, which is common in many types of tumors. An association between BECN 1 loss and HER2/NEU amplification has been documented in breast cancer. Thirty percent of breast cancers have HER2/NEU, human epidermal growth factor receptor 2, overexpression due to gene amplification and are associated with aggressiveness, poor clinical outcome, and chemotherapy resistance. HER2 signaling can activate both the RAS-MAPK and phosphoinositide 3-kinase (PI3K) pathways, which have been implicated in promoting or inhibiting autophagy, respectively. We generated autophagy-defective immortalized mouse mammary epithelial cells (iMMECs) stably overexpressing Her2 and compared them to autophagy-competent HER2-expressing iMMECs in 2D-culture, 3D-morphogenesis and tumorigenicity in nude mice. We performed functional autophagy assays and found that HER2-expressing iMMECs exhibited reduced levels of autophagy induction under metabolic stress compared to wildtype iMMECs. We also found that Becn1+/- iMMECs expressing HER2 formed tumors faster than their autophagy-competent counterparts, indicating a positive interaction between HER2 overexpression and deficient autophagy in mammary tumorigenesis. Allograft mammary tumors generated by HER2-expressing autophagy-competent and -deficient iMMECs were analyzed by gene expression profiling to identify pathways further promoting mammary tumorigenesis when HER2 overexpression and defective autophagy are combined. Cellular functions such as cell growth, proliferation, and cell death were found to be to be altered between HER2-expressing autophagy-competent and -deficient backgrounds using the gene expression profiling software Ingenuity Pathway Analysis (IPA). Identifying the key players of these pathways and their roles in tumorigenicity will help elucidate the interaction between autophagy and HER2 in mammary tumorigenesis. Given the recent emergence of autophagy as a novel therapeutic target in cancer treatment, understanding how the autophagy and HER2 pathways interact in mammary tumorigenesis is crucial for the development of new and more effective therapies for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3777. doi:10.1158/1538-7445.AM2011-3777