Role of Telomerase in Mammary Stem Cell Function
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: Telomerase is expressed in unspecialized mammary stem cells and progenitor cells (i.e., cells that have begun the path to specialization as ductal, lobular, or myoepithelial cells), but its role in these compartments is not fully understood. The standard thinking on the function of telomerase in these stem/progenitor cells is to counter loss of DNA that occurs at the chromosomal ends with each cell replication cycle. Overexpression of TERT, the protein catalytic component of telomerase, in human mammary epithelial cells results in telomere elongation and cellular immortalization. Telomerase is known to be reactivated in 90% of human breast cancers, where it is thought to serve a similar function in endowing these tumors with unlimited proliferative potential. However, recent data from my laboratory challenges this paradigm and indicates that TERT possesses other activities that do not depend upon its well-understood function in elongating telomeres. 
 
 
 
 
 
 
 
 In this study we will test the hypothesis that conditional activation of TERT in adult mouse mammary epithelium leads to increased proliferation and breast cancer by way of promoting proliferation or expansion of mammary stem/progenitor cells. We will also use genetic means to determine if these effects of TERT involve telomere synthesis.
 
 The aims are:
 
 1. To determine how conditional induction of TERT alters proliferation and development in the mammary gland. Using a novel tetracycline-inducible TERT system that we have engineered, we will activate TERT in the adult mammary gland to understand how TERT induces proliferation and breast cancer.
 
 2. To understand how TERT modulates mammary stem cell function. We will test if activation of TERT leads to expansion of stem/progenitor cells and if TERT extends serial transplantation by enhancing mammary stem cell function.
 
 
 
 
 
 
 
 We use a novel conditional transgenic system for inducing TERT in adult mammary epithelium with a tetracycline-regulated approach. Effects on mammary epithelium will be studied using whole mount (i.e., spreading and staining the whole tissue on glass slide) and histological (i.e., sectioning and microscopic) analyses. Proliferation will be assessed using BrdU incorporation and Ki-67 staining. Tumor formation will be studied by careful necropsy and histological analysis. The requirement for TERT's telomere synthesis function will be dissected genetically in a telomerase RNA component (TERC)-negative background. A potential effect on the mammary stem/progenitor compartments will be studied by Sca-1 and Keratin-6 staining, and by serially transplanting mammary epithelial into de-epithelialized hosts having their epithelial compartments removed.
 
 
 
 
 
 
 
 A detailed understanding of TERT's multiple functions in mammary stem cell function and in breast cancer may lead to novel therapeutic approaches to block these functions. For example, current anti-telomerase strategies aim to inhibit enzymatic function. In contrast, a more effective strategy might entail inhibiting TERT protein, or other elements in a potential TERT signaling cascade.