title: Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer.
abstract: Understanding the origins of resistance to anti-oestrogen drugs is of critical importance to many breast cancer patients. Recent experiments show that knockdown of GRP78, a key gene in the unfolded protein response (UPR), can re-sensitize resistant cells to anti-oestrogens, and overexpression of GRP78 in sensitive cells can cause them to become resistant. These results appear to arise from the operation and interaction of three cellular systems: the UPR, autophagy and apoptosis. To determine whether our current mechanistic understanding of these systems is sufficient to explain the experimental results, we built a mathematical model of the three systems and their interactions. We show that the model is capable of reproducing previously published experimental results and some new data gathered specifically for this paper. The model provides us with a tool to better understand the interactions that bring about anti-oestrogen resistance and the effects of GRP78 on both sensitive and resistant breast cancer cells.
authors: Department of Biological Sciences , Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA.
authors: Jignesh H
authors: JH
authors: Parmar
authors: Department of Oncology, Lombardi Comprehensive Cancer Center , Georgetown University Medical Center , Washington, DC 20057 , USA.
authors: Katherine L
authors: KL
authors: Cook
authors: Department of Oncology, Lombardi Comprehensive Cancer Center , Georgetown University Medical Center , Washington, DC 20057 , USA.
authors: Ayesha N
authors: AN
authors: Shajahan-Haq
authors: Department of Oncology, Lombardi Comprehensive Cancer Center , Georgetown University Medical Center , Washington, DC 20057 , USA.
authors: Pamela A G
authors: PA
authors: Clarke
authors: Department of Biological Sciences , Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA.
authors: Iman
authors: I
authors: Tavassoly
authors: Department of Oncology, Lombardi Comprehensive Cancer Center , Georgetown University Medical Center , Washington, DC 20057 , USA.
authors: Robert
authors: R
authors: Clarke
authors: Department of Biological Sciences , Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA.
authors: John J
authors: JJ
authors: Tyson
authors: Bradley Department of Electrical and Computer Engineering , Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA.
authors: William T
authors: WT
authors: Baumann
keywords: GRP78; anti-oestrogen resistance; autophagy; breast cancer; mathematical modelling; unfolded protein response