Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression

Abstract

The transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC, thereby suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells isolated from wild-type neu expressing mice and identified the E3 ligase HACE1 as HER2 cooperative tumor suppressor gene. Loss of HACE1 expression is commonly seen in clinical breast cancer data sets. HACE1 downregulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Rac1 partially transforming these cells. Overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. Although the knockdown of HACE1 or overexpression of HER2 alone in HMECs is not sufficient for tumorigenesis, HER2 overexpression combined with HACE1 downregulation fully transforms HMECs resulting in robust tumor formation. The pharmaceutical interference of Rac function abrogates the effects of HACE1 loss both in vitro and in vivo, resulting in marked reduction in tumor burden. Our work supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac-targeted therapies.

Overexpression of HACE1 in gastric cancer inhibits tumor aggressiveness by impeding cell proliferation and migration

“…HACE1 was found low expressed in previous studies about breast cancer , colorectal cancer , liver cancer and leukemia . In this study, we also spotted a significant down‐regulation of HACE1 in gastric cancer tissues compared with their adjacent normal tissues.…”

New miRNA expression abnormalities in laryngeal squamous cell carcinoma

“…HECT E3 ligase targets the Rac1 gene for subsequent proteosomal degradation and regulates cell motility and apoptosis [17]. Downregulation of HACE1 due to allelic loss or promoter hypermethylation, was reported in multiple human cancers such as gastric [34] and breast cancer [9], leading to enhanced Rac1 signalling and promoting cell invasion. Similarly, although our findings indicate HACE1 underexpression in laryngeal cancer tissue, the present study does not examine the mechanism of this alteration, and as a literature search reveals no other studies concerning the role of HECT E3 ubiquitin ligase in this type of cancer, further studies are needed to establish other HACE1 targets.…”

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

“…Consistent with the role of Rac in the control of NADPH oxidase complexes, deficiency in the tumor suppressor HACE1 increases reactive oxygen species (ROS) production, and this in turn leads to an addiction to Gln, a major nutrient source for tumor cells (26). Moreover, HACE1 down-regulation cooperates with ErbB2/HER2 overexpression in mammary cells to induce Rac1 hyperactivation, migration, malignant transformation, and tumorigenesis in vivo , effects that are sensitive to pharmacological Rac inhibition (27). A very recent report that identified cancer-associated missense mutations in HACE1 leading to defective Rac1 ubiquitination highlights the relevance of the control of Rac1 expression in cancer cell proliferation (28).…”