Abstract
Inhibition of epidermal growth factor receptor (EGFR) signaling is considered to be a promising treatment strategy for estrogen receptor (ER)-negative breast tumors. We have investigated here the anti-breast cancer properties of a novel anti-proliferative benzopyran compound namely, 2-[piperidinoethoxyphenyl]-3-phenyl-2H-benzo(b)pyran (CDRI-85/287) in ER- negative and EGFR- overexpressing breast cancer cells. The benzopyran compound selectively inhibited the EGF-induced growth of MDA-MB 231 cells and ER-negative primary breast cancer cell culture. The compound significantly reduced tumor growth in xenograft of MDA-MB 231 cells in nude mice. The compound displayed better binding affinity for EGFR than inhibitor AG1478 as demonstrated by molecular docking studies. CDRI-85/287 significantly inhibited the activation of EGFR and downstream effectors MEK/Erk and PI-3-K/Akt. Subsequent inhibition of AP-1 promoter activity resulted in decreased transcription activation and expression of c-fos and c-jun. Dephosphorylation of downstream effectors FOXO-3a and NF-κB led to increased expression of p27 and decreased expression of cyclin D1 which was responsible for decreased phosphorylation of Rb and prevented the transcription of E2F- dependent genes involved in cell cycle progression from G1/S phase. The compound induced apoptosis via mitochondrial pathway and it also inhibited EGF-induced invasion of MDA-MB 231 cells as evidenced by decreased activity of MMP-9 and expression of CTGF. These results indicate that benzopyran compound CDRI-85/287 could constitute a powerful new chemotherapeutic agent against ER-negative and EGFR over-expressing breast tumors.
Highlights
Breast cancer is the most common cancer diagnosed in women and the second most common cause of female cancer- related deaths [1]
In search for novel agents for successful therapies of breast cancer, epidermal growth factor family of receptors (EGFR) has long been used as a target for therapeutic intervention in estrogen receptor (ER)-ve as well as triple negative breast tumors that do not respond to endocrine therapy [1]
We have examined the effects of 2-[piperidinoethoxyphenyl] -3phenyl- 2H-benzo (b) pyran (CDRI-85/287) on EGFR -mediated signaling and cell survival/apoptosis in ER- negative human breast cancer cells and in xenograft mice model
Summary
Breast cancer is the most common cancer diagnosed in women and the second most common cause of female cancer- related deaths [1]. In ER- negative tumors, overexpression of EGFR or HER-2, leading to increased growth factor signaling, is observed [5]. A subgroup of ER-negative tumors is negative for the expression of progesterone receptor and HER-2 protein [6]. Such tumors are designated as ‘triplenegative’ and are characterized by their unique molecular profile, aggressive behavior and distinct patterns of metastasis. Overexpression of the epidermal growth factor family of receptors (EGFR) in ER- ve cells has been the basis for the implication of EGF-induced mitogenic signal for the enhanced proliferation of these cancer cells [7,8]. EGFR could serve as a target for therapeutic intervention in a subgroup of triple-negative breast cancer patients
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