Abstract
Breast cancer tumor with triple-negative receptors (estrogen, progesterone and Her 2, receptors) is the most aggressive and deadly subtype, with high rates of disease recurrence and poor survival. Here, we show that induction in cell surface GRP78 by doxorubicin and tunicamycin was associated with CHOP/GADD153 upregulation and increase in apoptosis in triple negative breast cancer tumor cells. GRP78 is a major regulator of the stress induced unfolded protein response pathway and CHOP/GADD153 is a pro-apoptotic transcription factor associated exclusively with stress induced apoptosis. The blocking of cell surface GRP78 by anti-GRP78 antibody prevented apoptosis, suggesting that induction of cell surface GRP78 by doxorubicin and tunicamycin is required for apoptosis. A better understanding of stress induction of apoptotic signaling in triple negative breast cancer cells may help to define new therapeutic strategies.
Highlights
Breast cancer is the most commonly diagnosed cancer among women worldwide [1, 2]
We first evaluated the effect of doxorubicin and taxotere on cell surface Glucose-regulated protein 78 kDa (GRP78) expression in the human breast cancer cell line, since we have previously shown that these drugs induced cell surface GRP78 expression in human colon cancer cells [32]
In this study we demonstrated a significant increase in cell surface GRP78 on the triple negative breast cancer (TNBC) MDAMB468 by doxorubicin and taxotere but not on the receptor positive BT474 cells which probably reached the maximum expression before treatment
Summary
The phenotypic manifestations of the disease differ in patients with diverse cancer subtypes that exhibit varied responses to different treatment modalities [3]. Breast cancers are divided into subgroups and subtypes based on the expression of three cell surface receptors: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2(HER2). When the three receptors are absent (triple-negative) or at low levels as in the basallike tumors, a poor prognosis is diagnosed [6]. The only option to treat triple negative breast cancer (TNBC) is non-specific and highly toxic chemotherapy or radiation therapy [7, 8]. TNBC is a complex disease that requires the combination of two or more targets with different signaling pathways for an optimal treatment approach [9]
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