HDAC6 as a Therapeutic Candidate in the Treatment of Inflammatory Breast Cancers.

摘要

Inflammatory Breast Cancer (IBC) is a rare, lethal, and understudied form of breast cancer. Although affecting 1-2% of the population, the remission rate is half that of the spectrum of other breast cancers, and most cases present in the advanced stages due to rapid undetectable development. Of the diagnosed cases, systemic chemotherapeutics are relatively ineffective in comparison to non-IBC breast cancer cases, indicating other unique mechanisms driving IBC progression. Historically, the specific sensitivities of a particular tumor type or subtype have been linked to genetic alterations that represent addiction hubs, such as hyperactivation of oncogenes due to mutation.;Although some efforts have been made to characterize the molecular fingerprint of inflammatory breast cancers (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. Using shRNA libraries, we performed an unbiased genome-wide loss-of-function screen comparing the gene functions required for survival of IBC and non-IBC cells. Histone deacetylase 6 (HDAC6) emerged as one of the top genes required for IBC cell survival and was further validated.;HDAC6 is vital in the cell's unfolded protein response (UPR) to clear misfolded or toxic protein, and IBC cells proved to be preferentially sensitive to this aspect of HDAC6 inhibition, displaying increased protein accumulation, ER stress indicators, and subsequent apoptosis upon failure to clear or refold accumulated proteins. These data indicate HDAC6 is a crucial gene required for IBC cell line survival, in part due to its function in IBC cell UPR. Furthermore, emerging orally bioavailable agents for HDAC6 inhibition make it a promising candidate towards tailored therapeutic implementation in IBC patient trials.