Human
breast cancer cell proliferation is regulated by
growth factors that bind to receptors with intrinsic
tyrosine kinase (TK) activity, including the
epidermal growth factor (
EGF) receptor. To determine whether inhibition of receptor TK activity inhibits
tumor growth, we studied the effects of a
tyrosine kinase inhibitor,
RG-13022, on cultured human
breast cancer cells.
RG-13022 represents a class of compounds which have been shown to inhibit preferentially the TK activity of the
EGF receptor in a cell-free system and also to inhibit
EGF-stimulated growth of cultured cells.
RG-13022 significantly inhibited
EGF-stimulated autophosphorylation of its receptor in two
breast cancer cell lines that have abundant, although not amplified,
EGF receptor content (MDA-231 and T47D).
RG-13022 also inhibited
EGF-stimulated
DNA synthesis and proliferation of T47D and MCF-7
breast cancer cells in a reversible and dose-dependent manner. Inhibition was observed at 0.1 microM, and it was maximal
at 10 microM. The effect was rapid (within 3 h), persisted for 18 h, and was partially reversed by 24 h at 1 microM. At 5 microM, inhibition persisted for more than 50 h. Inhibitory effects were also observed in a panel of
estrogen receptor-positive and
estrogen receptor-negative
breast cancer cell lines.
RG-13022 inhibited not only
EGF-induced growth but also growth stimulated by
insulin,
insulin-like growth factor I,
insulin-like growth factor II, or
transforming growth factor alpha.
RG-13022 also totally blocked
estrogen-stimulated phosphorylation of the
EGF receptor, as well as
estrogen-induced cell proliferation, suggesting that functioning TK pathways are required for
estrogen action. The TK inhibitor
RG-13022 is a potent inhibitor of hormonally regulated growth of human
breast cancer.
Tyrosine kinase inhibitors have the potential of providing a new strategy for the "endocrine
therapy" of
breast cancer.