A Novel Pathway Controlling Ribosomal Biogenesis in Breast Cancer
Abstract
The current proposal addresses two overarching challenges in breast cancer by (a) identifying what drives breast cancer growth and (b) developing novel strategies for treatment of metastatic breast cancer that may reduce toxicities of current therapeutics. Treatment of breast cancer patients with recurrent and/or metastatic disease presents a considerable challenge. The molecular mechanisms driving metastatic progression are important therapeutic targets, although these mechanisms are not fully understood. We discovered a novel molecular pathway that controls ribosome biogenesis and may drive cancer progression. Ribosomes are cellular factories for production of proteins and composed of four RNA molecules and over 80 proteins. Ribosome biogenesis consumes the majority of cellular resources and requires coordinated production of ribosomal RNA and proteins and assembly of ribosomal subunits. Advanced-stage breast cancers typically ramp up production of ribosomes. In aggressive breast cancers, Myc oncogene stimulates ribosome production by affecting biosynthesis of ribosomal proteins. Although the basic principles of the ribosome assembly are defined, the molecular mechanisms controlling ribosome biogenesis remain largely unknown. Our findings show that a cellular protein called TGF-beta-activated kinase-1 (TAK1) controls production of regulators of ribosome biogenesis such as RRS1. Inhibition of TAK1 induces ribosomal stress, a cellular response associated with a block in ribosome biogenesis. Compared to Myc, TAK1 does not affect production of ribosomal proteins. Thus, the TAK1-RRS1 pathway is a novel way to control ribosome production. Genetic data revealed that high RRS1 levels correlate with breast cancer progression and poor prognosis. We also found that TAK1 inhibition reduces viability of cancer cells and enhances toxicity of chemotherapeutic agent 5-fluorouracil against triple-negative breast cancer (TNBC) cells. Together, these findings suggest that the TAK1-RRS1 pathway may drive breast cancer progression and represent a valuable target in breast cancer. The current proposal will test the hypothesis that the TAK1-RRS1 pathway controls ribosome biogenesis and that inhibition of TAK1 can suppress breast cancer progression and enhance anti-cancer activity of therapeutic agents. RRS1 may contribute to the invasive and metastatic capacities of tumor cells. Three specific aims will assess the mechanistic details and clinical implications of our hypothesis. Aim 1: Define the molecular mechanism of TAK1-mediated control of ribosome biogenesis and RRS1. TAK1 inhibition impairs ribosome biogenesis, but the mechanism is currently unknown. We will explore the mechanism by which TAK1 regulates RRS1 and ribosome biogenesis using the novel CRISPR/Cas9 technology and RNA interference approaches. The consequences of an impaired TAK1-RRS1 pathway will be compared in non-tumor and tumor cells in order to better understand the overall impact of TAK1 inhibition in patients with breast cancer. Aim 2: Determine the contribution of the TAK1-RRS1 pathway to the metastatic potential of breast cancer cells. High levels of RRS1 correlate with poor prognosis, while the role of RRS1 in breast cancer is currently unknown. We will examine the contribution of RRS1 to invasive/metastatic potential of breast cancer cells. Aim 3: Evaluate novel TAK1 inhibitors in preclinical animal models. We plan on testing the efficacy of novel TAK1 inhibitors in combination with therapeutic agents targeting ribosome biogenesis such as 5-fluorouracil. Successful completion of the project would fill a gap in understanding of how breast cancer cells control ribosome biogenesis. The TAK1-RRS1 pathway may represent a novel mechanism that drives metastatic progression. The critical components of this mechanism are potential novel targets for anti-cancer therapy. The study should provide a set of new genetically modified cel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610669
Entities
People
- Andrei Bakin
Organizations
- United States Army