Mechanical stressors and age as regulators of telomerase
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: This award is jointly funded with the Anita Tarr Turk Fund for Breast Cancer Research of the Community Foundation for Monterey County.
 
 
 
 
 
 Non-technical overview of the research topic and relevance to breast cancer
 
 
 
 While there is no one cause of breast cancer, we have found that as women age, the cells responsible for maintaining healthy breast tissue stop responding to their immediate surroundings, including mechanical cues that should prompt them to suppress nearby tumors. The proposed research will address primary prevention of breast cancer by examining the microenvironmental regulation of a rate-limiting step in cancer progression, telomerase reactivation. We will examine how mechanical stressors and age regulate telomerase activity in normal human mammary epithelial cells (HMEC) to determine if the errors associated with early stage cancer progression decouple an association between stress and telomerase activity. Normal human breast epithelial cells possess limited replicative capacity, due to the presence of several distinct types of barriers that prevent proliferation and suppress tumor genesis. Breast cancer cells, on the other hand, possess an unlimited replicative potential, or immortality associated with the presence of telomerase, that maintains the chromosomal ends (telomeres). Malignant progression of a finite normal cell requires acquisition of errors that allow these tumor suppressive barriers to be bypassed or overcome. Using the unique, extensive HMEC culture system developed in our lab, our team will study the errors needed to bypass/overcome these barriers. If this hypothesis is true, it can open up new approaches to prevent or reverse how aging alters cellular and molecular functions that contribute to the prevalence of breast cancer in older women. Additionally, since immortality and its kind of telomerase regulation only occurs in abnormal transformed cells, it may be possible to ultimately identify therapeutics with minimal side effects that maintain normal telomerase regulation. 
 
 
 
 
 
 
 
 The question(s) or central hypotheses of the research: We are proposing that mechano-tensile forces within a cell, which are influenced by the external microenvironment, normally regulate telomerase; exposure to certain types of mechanical stressors will normally inhibit telomerase expression. Further, we hypothesize that early stage breast cancer progression is associated with errors that alter this normal process. When cells bypass stasis (a situation which would be similar to an initial oncogenic hit in normal breast progenitor cells, postulated to be a cancer cell of origin in vivo), the connection between stress and telomerase expression becomes decoupled, and such post-stasis cells are now vulnerable to errors that induce telomerase expression. Cells that overcame stasis require more errors to reactivate telomerase. Our proposal seeks to demonstrate this connection between stressors and telomerase, and uncover the mechanisms responsible for normal regulation and what changes when this connection is lost. 
 
 
 
 
 
 
 
 The general methodology: We will utilize cell culture substrata with tunable stiffness levels, a novel collection of HMEC strains that represent the progression from normal to immortal, and quantitative assays for telomerase expression and activity. With these resources we will determine whether mechanical stressors regulate telomerase in normal epithelial cells, and determine why that mode of control can become decoupled.
 
 
 
 
 
 
 
 Innovative elements of the project: Because expression of telomerase is essential for malignant progression, interventions that could prevent a decoupling of telomerase regulation by stressors, or restore this connection, could have a huge impact on reducing breast cancer incidence. We do not anticipate translational applications within the time frame of this grant; at this point our focus is to understand how mechanical stressors may regulate telomerase. Since the hypothesized decoupling occurs only in abnormal cells, our long-term goal is that once mechanisms are delineated, therapeutic interventions can be identified. Such clinical applications could prevent progression from pre-malignant lesions (DCIS, atypical hyperplasia) to primary or metastatic cancer.