Src Signaling in Breast Cancer
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: The v-Src (Rous sarcoma virus) tyrosine kinase was the first oncogenic gene discovered. The corresponding cellular gene, c-Src, is a non-receptor signaling kinase located at the cell membrane. The central hypothesis on which this research is based is that the Src tyrosine kinase and its effectors control not only cell proliferation, but also the pathways and genes that dictate cell polarity and tissue architecture. To explore this hypothesis we have teamed-up with colleagues, Dr. Mina Bissell’s group, at the Lawrence Berkeley National Laboratory. Breast cancer cells cultured in three-dimensional reconstituted basement membrane (3D-rBM) cultures revert to normal mammary ductal structures when signaling by the EGF-receptor (EGFR) or β1-integrins is inhibited. These findings have highlighted the importance of three-dimensional tissue architecture in the control of tumor cell proliferation. Both EGFR and integrin signaling pathways are known to be mediated by the non-receptor tyrosine kinase, Src. Furthermore, Src and some of its downstream effectors, such as the transcription factors Stat3 and Myc, are known to be increased in expression and/or activity in a variety of breast cancer types. Yet the detailed role of the Src-Stat3-Myc pathway in breast cancer and mammary cell biology remains uncertain.
 
 
 
 
 
 
 
 We hypothesize that an increase in the activity of Src or its effectors is sufficient to convert normal mammary epithelium into “tumor-equivalent” cells that cannot form normal mammary acini (def. Terminal Ductal Lobular Units TDLU or acini). We also hypothesize that a decrease in the function of Src or its effectors may be sufficient to induce reversion of tumorigenic cells to regain the ability to form normal mammary structures. To test these possibilities, we will use a normal mammary epithelial line, HMT-3522-S1, and its tumorigenic derivative HMT-3522-T4-2. We will determine whether blocking the function of Src, Stat3 or Myc is sufficient to cause reversion of tumorigenic mammary epithelial cells to form normal mammary acini in three-dimensional matrix cultures. To examine the effect of malignant conversion and reversion on the function of Src, Stat3 and Myc we will use antibodies or DNA probes to determine their level of expression, degree of activation, extent of phosphorylation, or in vitro activity. In addition, to determine the effect of an increase in the activity of Src or its effectors, we will introduce into normal mammary epithelial cells wild-type or ”activated” Src, Stat3 and Myc constructs under the control of an inducible promoter. 
 
 
 
 
 
 
 
 Src, Stat3 and Myc are all under active investigation in both academic and commercial settings as possible targets for anti-cancer therapy. Yet, the effect of inhibiting or activating Src signaling in normal or tumorigenic cells is not well understood. In particular, it is not clear whether this pathway regulates the morphogenesis of normal breast acini or whether inhibiting this pathway in tumorigenic cells can result in reversion to the normal phenotype.