THE ROLE OF AUTOCRINE HUMAN GROWTH HORMONE (HGH) IN HER2+ BREAST CARCINOMA CELLS

Abstract

Herein, this project determined the oncogenic capabilities of autocrine hGH in mediating malignant transformation and reducing sensitivity of HER2+ mammary carcinoma cells towards therapeutic agents such as Herceptin or Lapatinib in vitro. Functional in vitro assays demonstrated that forced expression of hGH significantly increases total cell number and enhances cell viability in 3D, and reduces apoptosis in BT474 and SkBR3 HER2-amplified mammary carcinoma cells. Anchorage-independent growth in soft agar is greatly enhanced in BT474 in the presence of autocrine hGH. One mechanism by which autocrine hGH exerts its oncogenic capacity in BT474 and SkBR3 is through stimulating tyrosine phosphorylation at Y1248 cytoplasmic residue, a major autophosphorylation site of HER2. Besides that, autocrine hGH provided selective growth advantage to BT474 and SkBR3 from Herceptin-induced growth inhibition than that of Lapatinb treatment. Functional inhibition of endogenous hGH using GHR antagonists (B2036 and G120R) was attempted to examine the synergistic effect of blocking GH signalling and inhibiting HER2 activity in HER2+ mammary carcinoma cells. Unfortunately, the cell line models used is either unresponsive to B2036 or selected out at early passage in the presence of G120R. Nevertheless, early passage stable cells transfected with G120R exhibited significant reduction in oncogenic capacity in proliferation and anchorage-independent growth, implying that blockage of circulating hGH is effective to decrease oncogenicity of HER2+ mammary carcinoma cells. Based on the experimental evidence, it suggests that hGH may play as additional prognostic marker and possess predictive role in HER2-overexpressing breast cancer. Nevertheless, more work is required to verify the use of GHR antagonists in combination with HER2-targeted therapies in HER2+ tumours.