Basal-like Breast Cancer (BLBC) represents the most aggressive sub-type of breast cancer with poor prognosis. As approximately 80% of BLBC lacks expression of hormone (estrogen and progesterone) receptors and human epidermal growth receptor 2 (HER-2), current treatment options are highly limited. Our long term goal is to understand the molecular signatures that make BLBC aggressive so that we can develop novel BLBC specific therapeutic intervention. The levels of integrin beta4 (ITG beta4) correlates significantly with Basal-like Breast Cancer (BLBC), suggesting that ITG beta4 is a candidate for the novel therapeutic target of BLBC. However, few attempts have been made to selectively disrupt ITG beta4 signaling important for metastatic potential without interrupting its normal functions. This is partly due to lack of understanding of negative signaling loop of ITG beta4. A recent report indicates that a potential tumor suppressor, arrestin domain-containing 3 (ARRDC3) interacts with ITG beta4 and negatively regulates its function by reducing ITG beta4 level. We found that ARRDC3 level is particularly low in BLBC cells and tissues compared to other sub-types of breast cancer. However, the signaling mechanism(s) that induces ARRDC3 dependent ubiquitination and degradation of ITG beta4, and the mechanism by which BLBC cells suppress the expression of ARRDC3 are currently unknown. In addition, no pharmacologic agent was developed to inhibit signaling competency of ITG beta4 yet. Our preliminary studies showed that ARRDC3 acts as an adaptor molecule to link ITG beta4 to a specific E3 ligase, and that ARRDC3 expression is epigenetically silenced in BLBC cells. We also established Cellomics based high throughput and high content screening of small-molecule based drugs that affect lipid raft incorporation of ITG β4, an essential event for signaling competency of ITG beta4, in BLBC cells. Based on these preliminary data, we formulate the hypothesis that BLBC prevents degradation of signaling competent ITG beta4 by suppressing ARRDC3 expression via epigenetic silencing. Therefore, restoration of ARRDC3 expression or prevention of ITG beta4 signaling competency in BLBC cells will block ITG beta4 dependent BLBC progression.
The first aim will perform mechanistic studies involving negative feedback regulation of ITG beta4 signaling by defining the mechanism of ARRDC3 dependent ubiquitination of ITG beta4 and subsequent degradation of this integrin.
The second aim will assess whether epigenetic silencing of ARRDC3 expression is linked to progression of BLBC by using 3D culture and xenograft models involving DCIS.com cells.
The third aim will test anti-cancer effects of small-molecule based drugs that block lipid raft-localization of ITG beta4 in BLBC model in vitro and in vivo.
Up to 37% of women with breast cancer have basal-like breast cancer (BLBC), an aggressive subtype for which no novel target-specific therapy is available. Recent reports suggest that expression of integrin beta4 (ITG beta4) is up regulated in BLBC, which suggest that this integrin contributes to the aggressive behavior of BLBC. Our preliminary studies led to the hypothesis that BLBC prevents NEDD4 dependent degradation of signaling competent ITG beta4 by suppressing the expression of tumor suppressor called ARRDC3 via epigenetic silencing. Therefore, restoration of ARRDC3 expression or prevention of ITG beta4 signaling competency in BLBC cells will block ITG beta4 dependent BLBC progression. The long term goal of this study is to establish ARRDC3-integrin beta4 pathway as a therapeutic target for BLBC, which is relevant to the mission of the NCI.
|Soung, Young Hwa; Pruitt, Kevin; Chung, Jun (2014) Epigenetic silencing of ARRDC3 expression in basal-like breast cancer cells. Sci Rep 4:3846|