HACD2, a Regulator of Bone-Resident Breast Cancer Cell Dormancy and Growth
Abstract
The bones are the most common site of metastatic breast cancer (BC) cells, and ~50% of patients with advanced BC develop bone metastases, a major cause of mortality and morbidity characterized by bone fracture and severe pain. BC metastasis to the bone is a multi-step process and the individual steps vary significantly among patients. Bone marrow is a major homing organ for dormant disseminated tumor cells (DTCs), and metastatic recurrence can occur in years to decades after initial treatment of primary tumors. These dormant DTCs are thought to be resistant to therapies and responsible for metastatic recurrence, the main cause of mortality in BC patients. Both estrogen receptor (ER)-positive and triple-negative breast cancer (ER-/PR-/Her2- TNBC) cells metastasize to the bones and enter dormancy. However, a long-lasting dormancy is especially pronounced in ER+ BC, suggesting that ER-mediated pathway may regulate the state of tumor dormancy. Through genome-wide knockdown of potential regulators of tumor dormancy and subsequent in vivo functional screening, we identified 3-hydroxyacyl-CoA dehydratase (HACD2) as a potential dormancy regulator for bone-resident tumor cells. HACD2 is involved in the productions of very long-chain fatty acids (VLCFAs). Our study provided evidence that HACD2 induces the expression of dormancy genes such as TGFBetaR, Axl, and BMPR and activates the dormancy signaling network involving secreted VLCFAs signaling. A review of the literature found that HACD2 is upregulated by ER. A correlation analysis using the TCGA BC cohort (n = 1104) showed a positive correlation between the expression levels of HACD2 and the dormancy signaling receptors TGFBetaRI, TGFBetaRII, TGFBetaRIII, BMPRII, and Axl, supporting clinical relevance of our study. This Breakthrough Award Level 1 application addresses the overarching challenge to understand why/how breast cancer cells lie dormant for years and then re-emerge and how to prevent lethal recurrence. In this application, we hypothesize that ER-regulated HACD2 induces tumor dormancy signaling networks in BC cells and regulates tumor-bone marrow niche interactions. To test this novel hypothesis, Aim 1 will determine the roles of HACD2 in the regulation of breast cancer cell survival, dormancy period, and tumor growth in the bones using a novel animal model. In addition, we will examine the bone marrow environment where BC cells home to and reside, and also investigate the role of HACD2 in the regulation of tumor-bone marrow niche interactions in the context of ER. Aim 2 will investigate VLCFA/free fatty acid receptor (FFAR) signaling pathways for the regulation of BC cell dormancy. We will also investigate HACD2-controlled dormancy signal transducers and their functional significance on BC interactions with the bone microenvironment. This Level 1 application focuses on the functions of HACD2 as a regulator of BC cell dormancy. The proposed study presents a new paradigm for the role of VLCFAs in the regulation of bone-resident BC cell dormancy. Identification and characterization of HACD2 will have high impact in the management of recurrent metastasis. This knowledge will provide the basis for novel therapeutic strategies that may involve FFAR- targeted therapy or VLCFAs supplements. Considering that FFAR agonists and antagonists are currently available and FFAR1 agonists have been tested in clinical trials for the treatment of type 2 diabetes, our study may lead to a breakthrough for patients with a high potential of recurrent metastasis in the relatively near future.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210057
Entities
People
- Hyeong-reh Kim
Organizations
- United States Army
- Wayne State University