Only about 30% of Her 2 expressing breast cancers respond to therapeutic antibodies and these cancers eventually become refractory to this therapy. These outcomes suggest that therapies targeting as yet unknown Her 2 related synergistic pathways remain to be elucidated and exploited for their therapeutic potential. These pathways may well involve local and systemic factors and pathways that affect Her2 oncogenesis. The model system used for these studies was primary mouse mammary tumor cells expressing MMTV-driven activated Her 2/neu cultured within collagen gels and in serum-free medium. A key factor enabling the proliferation of these cells in the absence of serum was lysophosphatidic acid (LPA). LPA's primary role was found to be that of a synergist allowing the growth-stimulatory potential of specific growth factors to be expressed. LPA had limited proliferative capacity alone but synergized with EGF, FGF-2 and FGF-7 to stimulate multifold (10-fold) proliferation in serum-free culture media. EGF alone could stimulate limited growth (2-fold) while FGFs-2, -7 alone were relatively less stimulatory to growth. Real time RTPCR shows that G protein-coupled LPA receptors (LPAR1, 2, 3) are expressed in the tumor cells. Furthermore, proliferative synergy between LPA and growth factors was inhibited by pertussis toxin, an inhibitor of Gαi signaling suggesting that this G-protein-coupled receptor pathway can have a critical impact upon Her 2/neu tumor cell proliferation. LPA receptors are also expressed in the stroma of mouse mammary glands raising the possibility that the growth and progression of Her 2/neu mammary tumors is potentially dependent upon synergistic interactions between bioactive lipids and growth factors, both of which can be synthesized locally as components of a stromal-epithelial regulatory network.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2505.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO