Blockade of Epidermal Growth Factor Receptors Chemosensitizes Breast Cancer Cells through Up-Regulation of Bnip3L

Abstract

Epidermal growth factor receptor-1 (EGFR) and EGFR-2 (HER2) have become major targets for cancer treatment. Blocking antibodies and small-molecule inhibitors are being used to silence the activity of these receptors in different tumors with varying efficacy. Thus, a better knowledge on the signaling pathways activated by EGFR and HER2 may help unravel novel therapeutic targets and molecular markers of response. Here, we show that treatment of breast cancer cell lines with blocking antibodies against EGFR (cetuximab) or HER2 (trastuzumab) promotes the specific induction of proapoptotic Bnip3L and chemosensitization. Moreover, we found that the Bnip3L gene is transcriptionally activated by FoxO3a. Trastuzumab-mediated induction of Bnip3L and nuclear translocation of FoxO3a was also shown in pleural effusion cells from a breast cancer patient. Transfection of breast cancer cells with constitutively active FoxO3a or with Bnip3L promotes sensitization to chemotherapy-induced apoptosis. On the contrary, blockade of Bnip3L expression by a small interfering RNA strategy significantly diminished the chemosensitizing effect of cetuximab. We found also an inverse correlation between EGFR and Bnip3L expression in surgical specimens from patients with breast cancer. Therefore, blockading EGFR or HER2 specifically up-regulates Bnip3L, which is required for chemosensitization of breast cancer cells. This novel pathway provides also the rationale for therapeutic strategies aimed to induce the expression of Bnip3L. (Cancer Res 2005; 65(18): 8151-7)

HER1-ECD vaccination dispenses with emulsification to elicit HER1-specific anti-proliferative effects

“…Akt/PKB inhibition, as a consequence of EGFR blockade reduce the activation levels of antiapoptotics proteins such as Bax, BAD and Binp3L, enhancing apoptotics signals. [24][25][26] These effects have been reported in tumor cell lines treated using the EGFR blocking agents cetuximab and gefitinib, also demonstrating the abrogation of anti-apoptotic protein Bcl-X L . 27 Nevertheless, further experiments should be conducted to elucidate whether apoptosis plays an essential role as a death mechanism.…”

Knockdown of FLOT1 Impairs Cell Proliferation and Tumorigenicity in Breast Cancer through Upregulation of FOXO3a

“…Overexpression of FOXO3a can suppress the proliferation and tumorigenesis in athymic mice (24). Enhancement of FOXO3a transactivity on treatment with MAPKK inhibitor, EGFR antibody (cetuximab)/HER2 antibody (trastuzumab), or paclitaxel induces apoptosis of breast cancer cells, indicating that FOXO3a plays an important role in inhibiting development and progression of breast cancer (25)(26)(27). Meanwhile, inhibition of FOXO3a activity mediated by IkB kinase increases resistance to apoptosis and promotes tumor growth in nude mice, suggesting that activation of FOXO3a may be a potential therapeutic intervention strategy for breast cancer (28).…”

Targeting EGFR and HER-2 with cetuximab- and trastuzumab-mediated immunotherapy in oesophageal squamous cell carcinoma

“…It has been shown that treatment with cetuximab or trastuzumab for breast cancer cells promoted the specific induction of pro-apoptotic molecules and resulted in the upregulation of chemosensitisation (Real et al, 2005). Furthermore, it has been reported that EGFR-HER-2 heterodimers are rate-limiting in the EGF-mediated proliferation of tumour cells (Hsieh et al, 2000).…”