Growth factors and their receptors are important in the regulation of cancer cell proliferation. An increased proliferation rate of human breast tumors correlates with a both a decreased relapse-free survival time and overall patient survival. Human and animal studies point to a causative role for epidermal growth factor receptor (EGFR) and erbB2 signaling in the development and progression of approximately 30 percent of breast cancers. The erbB2 proto-oncogene (also known as HER2 or neu) is closely related to the EGFR, and like the EGFR is overexpressed in nearly 30 percent of human breast cancers. Experimental evidence has shown that guanine nucleotide-binding proteins (G-proteins), participate in the coupling of receptor binding to activation of effector molecules involved in cell proliferation. Both the EGFR and erbB2 possess a common putative cytosolic G-protein binding sequence. We and others have demonstrated the involvement of a pertussis toxin-sensitive G- protein in EGFR-mediated cell proliferation of breast cancer. We have identified a novel mechanism whereby this G-protein association with the EGFR is linked to breast cancer cell proliferation. We further demonstrate that fatty acids can modulate EGF induced breast cancer cell proliferation via this EGFR/G-protein signaling pathway. Studies indicate that this G- protein may have unique properties and therefore may be a novel G-protein. We propose to first identify the specific G-protein associated with the EGFR by purification, sequencing and cloning if it is novel. Secondly we shall characterize the growth regulatory intracellular signaling pathway which will be important to target future therapies and understand the regulation of EGF/erbB2 induced cell proliferation. Finally we shall demonstrate whether this signaling mechanism is specific for breast cancer cells and whether it is activated by erbB2 and if so can the erbB2/G-protein association, like the EGFR/G- protein association be modulated by fatty acids. This cancer growth regulatory pathway may represent an underlying regulatory pathway common to other types of cancer also linked to EGFR and erbB2 upregulation. Defining this novel pathway whose upregulation is closely linked with breast cancer progression, may also identify novel therapeutic targets for dietary and pharmacological interventions.
| Li, Chuanyu; Zhao, Xiangmin; Toline, Eric C et al. (2011) Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate. Carcinogenesis 32:1251-8 |
