Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

Abstract

The heregulins are a family of ligands with ability to induce phosphorylation of the p185 HER-2/neu receptor. Various investigators have reported a variety of responses of mouse and human breast and ovarian cells to this family of ligands including growth stimulation, growth inhibition, apoptosis and induction of di erentiation in cells expressing the HER-2/neu receptor. Some of the disparity in the literature has been attributed to variations in the cell lines studied, ligand dose applied, methodologies utilized or model system evaluated (i.e. in vitro or in vivo). To evaluate the e ects of heregulin on normal and malignant human breast and ovarian epithelial cells expressing known levels of the HER-2/ neu receptor, this report presents the use of several di erent assays, performed both in vitro and in vivo, in vitro proliferation assays, direct cell counts, clonogenicity under anchorage-dependent and anchorage-independent conditions, as well as the in vivo e ects of heregulin on human cells growing in nude mice to address heregulin activity. Using a total of ®ve di erent biologic assays in nine di erent cell lines, across two di erent epithelia and over a one log heregulin dose range, we obtained results that clearly indicate a growth-stimulatory role for this ligand in human breast and ovarian epithelial cells. We ®nd no evidence that heregulin has any growth-inhibitory e ects in human epithelial cells. We also quantitated the amount of each member of the type I receptor tyrosine kinase family (RTK I, i.e. HER-1, HER-2, HER-3 and HER-4) in the cell lines employed and correlated this to their respective heregulin responses. These data demonstrate that HER-2/neu overexpression itself a ects the expression of other RTK I members and that cells expressing the highest levels of HER-2/neu have the greatest response to HRG.

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

“…Up-regulation of ErbB-2 has been shown to increase proliferation, invasion, and migration in several human cancers (26,60), and studies in SKOV3 cells document a correlation between increased ErbB-2 protein expression and increased proliferation (47,48). However, in our SKOV3-based model system coexpressing LHR and ErbB-2, the LH-induced upregulation of ErbB-2 was insufficient in overcoming the negative effects of LHR on invasion, proliferation, or woundinduced migration and did not correlate with a more aggressive phenotype.…”

The ERBB3 receptor in cancer and cancer gene therapy

“…Most studies have focused on NRG effects. NRG is mitogenic for most mammary carcinoma cell lines, 82,[222][223][224][225] and can also stimulate motility and invasiveness of these cells. 209,[225][226][227] In ERBB2-over-expressing breast tumor cells, G1 progression after NRG stimulation was associated with ERBB2 transactivation of ERBB3 and stimulation of the PI3K pathway.…”

“…However, while high expression of NRG in mammary cancers may often contribute to their malignant phenotype, 224 a universal protumorigenic role for NRG in mammary cancer cannot be assumed. During development of the mammary gland NRG1α is the main form expressed, and is necessary for differentiation as well as proliferation.…”

Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients

“…Nevertheless the role of HRG in vivo remains to be explained. This factor has been associated in vitro with induction of cell proliferation (Holmes et al, 1992;Aguilar et al, 1999), invasion (Hijazi et al, 2000), apoptosis (Daly et al, 1997), differentiation (Peles et al, 1992;Bacus et al, 1993) and inhibition of cell proliferation (Hamburger and Yoo, 1997;Xu et al, 1997).…”