Abstract 2291: Inhibition of c-Src restores estrogen stimulated growth in estrogen-deprivation resistant MCF-7 breast cancer cells

Abstract

Abstract Resistance to aromatase inhibitors used for the treatment of estrogen receptor (ER) positive breast cancer is an increasing clinical problem. Previously we showed that physiological concentrations estradiol (E2) could trigger apoptosis of long-term E2 deprived breast cancer cells (MCF-7:5C) (Lewis et al. JNCI 2005; 97:1746-59). This new targeted strategy provides novel therapeutic approaches to endocrine resistant breast cancer. A recent phase II clinical trial reported that E2 provided a clinical benefit for aromatase inhibitor-resistant advanced breast cancer patients. However, only 30% of patients receive clinical benefit (Ellis MJ et al. JAMA 2009;302:774-80). This prompted us to investigate strategies to increase the therapeutic responsiveness in aromatase inhibitor resistant breast cancer. c-Src is currently of interest, as it mediates survival pathways of breast cancer cells. Here, we investigate the therapeutic potential of combination c-Src inhibitor PP2 and E2 on the MCF-7:5C cells. In the short-term treatment, c-Src inhibitor could block both Akt and MAPK pathways and decreased growth rates of MCF-7:5C cells. c-Src inhibitor could continuously block phosphor-Akt, but phosphor-MAPK pathway was increased after long-term treatment. Long-term treatment with E2 alone initially caused massive apoptosis, but a small population of surviving cells subsequently re-grew. In contrast, a combination of PP2 and E2 actually blocked apoptosis and the resulting cell line (MCF-7:PF) was unique, as they grew vigorously in culture with physiological levels of E2, which could be blocked by the pure antiestrogen ICI182,780. The mechanistic change underlying the action of combination treatment was that the c-Src inhibitor blocked E2 initiated apoptosis and collaborate with E2 to up-regulate endogenous ERα target genes and insulin-like growth factor-1 receptor (IGF-1Rβ) in MCF-7:PF cells. Furthermore, the inhibitor of IGF-1Rβ, AG1024, completely blocked E2 stimulated growth. This provides the evidence that IGF-1Rβ plays an important role in E2 stimulated growth in MCF-7:PF cells. These data illustrate that caution must be exercised when considering the evaluation of c-Src inhibitors in clinical trial following the development of acquired resistance to aromatase inhibitors, especially in combination with physiological levels of E2. Key words: c-Src, long-term estrogen deprivation, apoptosis, breast cancer Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2291. doi:10.1158/1538-7445.AM2011-2291