Felice, Dana / L, El-Shennawy, Lamiaa, Zhao, Shuangping, Lantvit, Daniel / L, Shen, Qi, Unterman, Terry / G, Swanson, Steven / M and Frasor, Jonna (2013) Growth Hormone potentiates 17beta-estradiol-dependent breast cancer cell proliferation in an IGF-I-independent manner. Endocrinology.

Abstract

Estrogen action in mammary gland development and breast cancer progression is tightly linked to the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. In rodents, both estradiol (E2) and GH are necessary for gland development and carcinogenesis. However, to what extent the effects of GH are mediated by IGF-I is unclear. Here, we demonstrate in Spontaneous Dwarf rats, which lack endogenous GH, that both GH and estradiol (E2) are critical to maintain proliferation of normal and cancerous mammary epithelial cells. In T47D human breast cancer cells, GH significantly enhances E2-stimulated proliferation. While the in vivo effects of GH may be direct on mammary epithelial cells and/or mediated by increased IGF-I, GH action in T47D cells was independent of IGF-I expression and IGF-IR signaling, suggesting that GH also may exert direct effects on breast cancer cells. Use of an IGF-IR inhibitor demonstrated that while E2-dependent proliferation required IGF-IR signaling, the combination of GH+E2 overcame IGF-IR blockade, restoring proliferation. In contrast, studies with specific inhibitors indicate that GH action through both Jak2 and EGFR was required for subsequent ERK activation and was essential for potentiation of E2-dependent proliferation. Downstream of these pathways, we identified a number of immediate early response genes associated with proliferation that are rapidly and robustly up-regulated by GH. Taken together, these findings demonstrate that GH can have important effects in breast cancer cells that are distinct from IGF-I, suggesting that novel drugs or improved combination therapies targeting ER and the GH/IGF axis may be beneficial for breast cancer patients.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9306