Elucidating the Determining Roles of the Newly Identified Long Noncoding RNA lncKCNJ3 in Triple-Negative Breast Cancer Pathogenesis
Abstract
Background, Rationale, and Aims: The spread of cancer cells occurs in the overwhelming majority of breast cancer patients, but is the least understood component of breast cancer biology. A better understanding of how metastatic dissemination manifests would reveal critical components of this process and would help develop new therapeutic strategies that save patients lives. Recent advances in cancer research have indicated that cancer cells within tumors exist within a hierarchy in which only a small subset of cells is able to spread and give rise to metastatic growths in secondary organs. These highly malignant cancer cells, which behave like stem cells for new cancers and are dubbed "cancer stem cells" or CSCs, have been shown to possess increased resistance to therapeutics and are thought to be the root cause underlying cancer recurrence and malignancy. Triple-negative breast cancers (TNBCs) encompass a subset of ~20% of diagnosed breast cancers and are characterized by the absence of hormone receptors, such as those for estrogen or progesterone. TNBCs represent an aggressive form of breast cancer, which is usually diagnosed late in its progression and to which no current targeted therapies exist. Patients identified with TNBC have >50%-60% chances of not responding to current therapies, and such refractory patients have dismal outcomes. Therefore, therapies directed against TNBC progression and therapy resistance are deeply needed, but remain elusive. To identify critical regulators of TNBC pathogenesis, we utilized a model of TNBC we have recently developed to analyze the genetic elements of TNBC CSCs. These efforts led to the identification of a new RNA molecule we called lncKCNJ. LncKCNJ belongs to a family of long non-coding RNAs (lncRNAs), a recently identified family of non-protein-coding RNAs shown to represent >20% of our genome and demonstrated to act as critical rheostats in homeostasis and in disease. Although lncRNAs tightly associate with cancer development, their functional contributions to breast cancer pathogenesis in general, and TNBC in particular, have not been described, and we set out to determine the contributions of lncKCNJ to TNBC pathogenesis. We show that lncKCNJ is particularly enriched in clinical TNBC and that it triggers features present in highly metastatic and tumor initiating cells responsible for therapy resistance and recurrence. We therefore hypothesize that lncKCNJ performs critical functions in TNBC malignancy, and here we aim to: (1) establish lncKCNJ as a clinically relevant prognostic biomarker in TNBC patients and as a therapeutic target in preclinical models and (2) determine the regulatory elements underlying lncKCNJ expression and functions. Our objective is for these studies to bring about novel proof-of-principle approaches for the management of advanced TNBC, for which no curative therapy currently exists. Overarching Challenges: Our data strongly indicate that lncKCNJ critically regulates TNBC malignancy. Therefore, characterization of the activities and functions of lncKCNJ as a major enhancer of metastasis will stand to (1) identify what drives breast cancer growth; determine how to stop it; and (2) identify why some breast cancers become life-threatening metastasis. Additionally, our proposed studies will test the feasibility of lncKCNJ inhibition as a valid anti-neoplastic approach using preclinical cellular and animal models, offering new translational methodologies to manage metastatic disease and stand to help (3) eliminate the mortality associated with metastatic breast cancer. Translational Ramifications: The characterization of novel determinants of breast cancer relapse and therapy resistance will provide critical insights into the fundamental mechanisms behind breast-cancer-associated mortality. The success of our proposed aims will have a number of translational outcomes: (1) provide proof-of-principle preclinical evidence that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710028
Entities
People
- Antoine E Karnoub
Organizations
- Beth Israel Deaconess Medical Center
- United States Army