Inflammatory breast cancer (IBC) is the most lethal form of breast cancer (~5% of all breast cancers). Almost all women with primary IBC have lymph node involvement, and at diagnosis approximately 25% have already distant metastases. Remarkably, the 5-year survival rate is only 40%, compared to the 85% survival rate among non-IBC patients. Despite its lethality, IBC remains poorly understood, and is the only breast cancer form for which mortality has continued to increase during the last 20 years. There are no current targeted therapies specific for IBC and systemic disease management relies mainly on chemotherapy.
Due to their unique biology the homeostasis of cancer cells present different requirements from non-transformed cells. Importantly, interfering with these requirements has been successfully used as a highly selective and low toxic anticancer strategy. Although some efforts have been made characterizing the molecular fingerprint of IBCs unfortunately, no clinical application has emerged from these studies. Thus, we decided to utilize a different strategy to identify the Achilles' heel of IBC cells. We have pioneered the development of genetic tools as well as experimental and analytical strategies to perform RNAi-based loss-of-function studies at a genome-wide level. Importantly, we and others have demonstrated that these functional screens are able to identify essential functions linked to certain cancer phenotypes. Specifically in breast cancer cells, these studies have revealed specific sensitivities associated to luminal and basal subtypes as well as individual mutated bona-fide cancer genes. Thus, we decided to use this approach to identify IBC specific sensitivities.
Through a genome-wide RNAi screen, we found and validated that the viability of IBC cells depends on histone deacetylase 6 (HDAC6) function. HDAC6 is a class-IIb histone deacetylase located mainly in the cytosol which displays diverse functions through the deacetylation of multiple targets. During the last decade, HDAC6 has emerged as a master regulator of the cell's protective response to cytotoxic accumulation of toxic bioproducts. Importantly, small molecule inhibitors for HDAC6 already exist and are currently being tested in advanced clinical trials for other tumor types. Here, through in vitro and in vivo preclinical studies, we demonstrated that Ricolinostat (ACY1215), the leading HDAC6 inhibitor, efficiently controls the progression of IBC. Thus, our findings represent an exciting opportunity to develop novel, efficient and well-tolerated toxic targeted therapeutic strategies for IBC patients.
Note: This abstract was not presented at the conference.
Citation Format: Preeti Putcha, Jiyang Yu, Ruth Rodriguez-Barrueco, Andrea Califano, jose silva. HDAC6 activity is a non-oncogene addiction hub for in inflammatory breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A71.