Abstract
<p class="Abstract">Breast cancer is the most common type of cancers and second primary cause of death among women. Insulin-like growth factor I (IGF-1) signaling pathway plays a vital role in cancer cell survival, proliferation, chemotaxis and angiogenesis. In this study, the effect of combination of two drugs, paclitaxel and trastuzumab on IGF signaling and cell cycle arrest in breast cancer cell lines, T47D and Hs0578T were explored. The interaction of paclitaxel and trastuzumab on IGF-1 signaling pathway was studied with IGF-1 and phosphoinositide 3-kinase inhibitor, LY294002. The protein expression of IGF signaling molecules were reduced in the drug treated cancer cells. LY294002 and IGF-1 with paclitaxel and trastuzumab treatment inhibited phosphorylated Akt. During G0/G1 phase, cell cycle arrest and accumulation of apoptotic cells were observed in drug treated cancer cells. The synergistic effect of paclitaxel and trastuzumab decreased the multiplication of breast cancer cells by altering the expression of IGF-I signaling molecules. This combination proves to be one of the useful methods to treat breast cancer.</p><p> </p>
Highlights
Insulin-like growth factor I receptor (IGF-1R) is a receptor tyrosine kinase (RTK) protein overexpressed in breast cancer cells (Nielson et al, 2004; Sachdev et al, 2004)
We investigated the cell cycle arrest and inhibition of cell proliferation by drug treatment was studied on estrogen receptor alpha positive (ER+) human breast cancer line, T47D and ER- human breast cancer cell line, Hs0578T
Primary antibodies for IGF signaling molecules, proliferative cell nuclear antigen (PCNA), cMyc, p21 and cyclin, LY294002 and β-actin antibody were purchased from Cell Signaling Technology (CST) and Santa Cruz Biotechnology (USA)
Summary
Insulin-like growth factor I receptor (IGF-1R) is a receptor tyrosine kinase (RTK) protein overexpressed (about 70%) in breast cancer cells (Nielson et al, 2004; Sachdev et al, 2004). IGF-1R is one of such receptors which consists of two α-subunits involved in ligand binding outside the cell and two β-subunits with a tyrosine kinase, TM domain and carboxyl terminal domain (Ullrich et al, 1986). The role of IGF-1 in breast cancer has been proved by several clinical studies (Li et al, 2001; Michels and Willett, 2004). The number of studies have been on the rise to elucidate the IGF1 function with breast cancer (Sarfestein et al, 2012; Becker et al, 2011; Kang et al, 2012). In one of the pathway, IGF-1 activates Raf and mitogen-activated protein kinase (MAPK) resulting in the transcription of proliferative genes whereas the second pathway involving phosphoinositide 3-kinase (PI3K)/Akt is responsible for cell survival and signaling of anti-apoptosis (Manning and Cantley, 2007)
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