Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer

Abstract

The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorageindependent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.

αVβ3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer

“…In order to address if HRG is regulating, at least in part, a v b 3 expression through CYR61 in MDA-MB-231 cells, we have first Discussion a v b 3 integrin overexpression in tumor cells is associated with malignant progression in breast and ovarian carcinomas as well as in glioma and melanomas (Rolli et al, 2003). In the present work, we demonstrate that HRG regulates, at least in part, the expression and the functions of the integrin receptor a v b 3 in two aggressive breast cancer cellular models (MDA-MB-231 and (Tsai et al, 2003). The levels of a v b 3 integrin in MDA-MB-231 and Hs578T cells expressing the antisense HRG cDNA were downregulated when compared to their parental counterparts.…”

“…Moreover, we have later shown that blockade of HRG in MDA-MB-231 cells inhibited cell proliferation, abolished anchorage-independent cell growth and suppressed the invasive potential of cells in vitro. In vivo, inhibition of HRG expression reduced tumor formation, size and metastatic ability of MDA-MB-231 cells (Tsai et al, 2003). Interestingly, MCF-7 cells genetically engineered to express HRG show an increase in a v b 3 levels (Tsai et al, 2000).…”

“…In the breast cancer scenario, we have shown a positive correlation between a v b 3 integrin levels and overexpression of HRG a member of the epidermal growth factor (EGF)-like growth factor family associated with breast cancer tumor progression and metastasis (Tang et al, 1996;Tsai et al, 2000Tsai et al, , 2003Atlas et al, 2003;Menendez et al, 2003). Moreover, we have demonstrated that forced expression of the HRG downstream effector, CYR61, is sufficient to promote acquisition of hormone independence and antiestrogen resistance in breast cancer cells (Tsai et al, 2002).…”

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

“…However, the nature of the signal generated by ErbB receptor complexes is not only dependent upon the repertoire of ErbB receptors expressed by tumors but also the ErbB receptor ligands expressed in the tumor microenvironment. HRG, an ErbB3/ErbB4 ligand, is expressed in the microenvironment of many tumors, notably breast cancer (Tsai et al, 2003). Our data suggest that HRG, but not EGF, activates p95 ErbB2 -ErbB3 heterodimers, which has downstream effects on AKT activation and clinical implications related to disease progression and resistance to therapy.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…87 Later approaches employed monoclonal antibodies to NRG. Some of the mAbs show synergy with chemotherapy on lung cancer cells.…”