Abstract 3923: Growth hormone activates ERK via EGFR, not IGF-IR, to potentiate estrogen-dependent breast cancer cell proliferation

Abstract

Estrogen receptor (ER) and insulin-like growth factor-I receptor (IGF-IR) interact and activate one another in breast cancer cells, and ER can up-regulate components of the IGF-I signaling pathway. Therapeutic strategies co-targeting ER and IGF-IR in ER-positive breast tumors have been developed, yet clinical trials of anti-IGF-IR therapies have not been as successful as had been hoped. Although growth hormone (GH) is implicated in having a role in breast cancer, its effects are often attributed to the actions of IGF-I. Since inhibition of IGF-IR can cause an increase in circulating levels of GH, we considered the possibility that GH may act directly on the tumor itself thus explaining the limited efficacy of anti-IGF-IR therapy in breast cancer. Therefore, we sought to determine whether GH has direct, IGF-I-independent effects on breast cancer. We demonstrate in T47D human breast cancer cells that while GH alone only weakly stimulates cell proliferation, it significantly enhances estradiol (E2)-stimulated proliferation. Inhibition of IGF-IR reduced E2-stimulated proliferation, confirming previous findings. Remarkably, GH+E2 overcame the IGF-IR blockade to promote proliferation. This indicates that GH not only acts in an IGF-I-independent manner, but can bypass IGF-IR inhibitors to restore E2 action on proliferation. Furthermore, we found that both epidermal growth factor receptor (EGFR) and ERK were required for proliferation stimulated by GH and E2, and that GH uses EGFR to activate ERK even in the presence of the IGF-IR inhibitor. Expression of proliferation genes up-regulated by GH+E2 treatment was abrogated by the EGFR and MEK inhibitors, but not by the IGF-IR inhibitor. Thus, we propose that while E2-stimulated proliferation requires IGF-IR, EGFR, and ERK, the presence of GH allows E2 to bypass the requirement for IGF-IR while remaining dependent on EGFR and ERK. Furthermore, we have found that GH can potentiate E2 stimulation of ER target gene transcription and this is dependent on ERK, but not on IGF-IR. Taken together, these findings indicate that GH not only can act directly on breast cancer cells independently of IGF-I, but can bypass IGF-IR blockade to stimulate ERK and potentiate E2 activity on proliferation and gene regulation. A better understanding of the interactions between GH and E2 will contribute to the development of novel drugs or improved combination therapies targeting the GH/IGF/E2 axis in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3923. doi:1538-7445.AM2012-3923