Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

Parmar, Jignesh H.; Cook, Katherine L.; Shajahan-Haq, Ayesha N.; Clarke, Pamela A.G.; Tavassoly, Iman; Clarke, Robert; Tyson, John J.; Baumann, William T.

doi:10.1098/rsfs.2013.0012

Cited by 27 publications

(21 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). GRP78 expression has been linked to drug resistance and malignancy in brain (25,26), liver (27,28), lung (29), and breast cancers (30,31). Our studies extend these findings by showing the prevalence and clinical significance of GRP78 expression in PDAC.…”

Section: Discussionsupporting

confidence: 75%

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Gifford

Huang

Zeleniak

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal. Although gemcitabine (GEM) is the standard chemotherapeutic agent for adjuvant therapy of resectable PDAC, recurrent disease is observed in an alarming number of GEM-treated patients. Regardless of the adjuvant therapy, the vast majority of patients treated with chemotherapy after surgical resection show tumor recurrence. A better understanding of the molecular mechanisms that contribute to chemoresistance would aid the development of more effective treatment strategies. GRP78 is an endoplasmic reticulum (ER) chaperone protein that primarily resides in the lumen of the ER and is the master regulator of the unfolded protein response (UPR). Here, we report that expression of GRP78 is significantly higher in GEM-resistant PDAC compared to GEM-sensitive PDAC patient samples. We show that GRP78 induces chemoresistance in PDAC cells. Our results also show that knockdown of GRP78 reduces chemoresistance in PDAC. Finally, we found that IT-139, a ruthenium-based anticancer drug, can overcome GRP78-mediated chemoresistance. In vitro, IT-139 restores sensitivity to cytotoxic drugs in drug-resistant PDAC cells and induces twice as much cell death in combination treatment compared with GEM alone. In vivo, a single weekly IT-139 treatment in combination with GEM caused a 35% increase in median survival and a 25% increase in overall survival compared to GEM alone. Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies, blocking the activity of GRP78 increases the efficacy of currently available therapies.

show abstract

Section: Discussionsupporting

confidence: 75%

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Gifford

Huang

Zeleniak

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Estrogen, which also induces significant protein production in breast cancer cells, elicits a similar response using this “non-canonical” signaling [156]. Consistent with our earlier studies in breast cancer, antiestrogens and estrogen withdrawal activate UPR components [59,148,157–160] including regulation through AMPK/mTOR signaling [161]. …”

Section: New Insights From a Systems Biology Viewsupporting

confidence: 72%

“…Expression of XBP1 and NFκB are correlated in breast cancer [168], and the prosurvival actions of XBP1 likely require its ability to activate NFκB [165]. As the most upstream regulator of canonical UPR signaling, the role of GRP78 in endocrine resistance has been strongly supported [59,70,161,180] and an initial mathematical model of its signaling has been described [160]. Importantly, GRP78 has been reported as a therapeutic target in several cancers [181,182].…”

Section: New Insights From a Systems Biology Viewmentioning

confidence: 99%

Endocrine resistance in breast cancer – An overview and update

Clarke

Tyson

Dixon

2015

Molecular and Cellular Endocrinology

Self Cite

297

252

View full text Add to dashboard Cite

Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects.

show abstract

“…Autophagy can be either prosurvival or prodeath (6, 18, 39). GRP78‐mediated autophagy is critical for desensitizing LCC1 cells to antiestrogens (5, 9). Moreover, MCF7 endocrine‐sensitive breast cancer cells serially treated with increasing doses of TAM exhibit increased prosurvival autophagy (21).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of estrogen receptor‐α induces autophagy and inhibits antiestrogen‐mediated unfolded protein response activation, promoting ROS‐induced breast cancer cell death

Cook

Clarke

Parmar³

et al. 2014

FASEB j.

Self Cite

View full text Add to dashboard Cite

Approximately 70% of all newly diagnosed breast cancers express estrogen receptor (ER)-α. Although inhibiting ER action using targeted therapies such as fulvestrant (ICI) is often effective, later emergence of antiestrogen resistance limits clinical use. We used antiestrogen-sensitive and -resistant cells to determine the effect of antiestrogens/ERα on regulating autophagy and unfolded protein response (UPR) signaling. Knockdown of ERα significantly increased the sensitivity of LCC1 cells (sensitive) and also resensitized LCC9 cells (resistant) to antiestrogen drugs. Interestingly, ERα knockdown, but not ICI, reduced nuclear factor (erythroid-derived 2)-like (NRF)-2 (UPR-induced antioxidant protein) and increased cytosolic kelch-like ECH-associated protein (KEAP)-1 (NRF2 inhibitor), consistent with the observed increase in ROS production. Furthermore, autophagy induction by antiestrogens was prosurvival but did not prevent ERα knockdown-mediated death. We built a novel mathematical model to elucidate the interactions among UPR, autophagy, ER signaling, and ROS regulation of breast cancer cell survival. The experimentally validated mathematical model explains the counterintuitive result that knocking down the main target of ICI (ERα) increased the effectiveness of ICI. Specifically, the model indicated that ERα is no longer present in excess and that the effect on proliferation from further reductions in its level by ICI cannot be compensated for by increased autophagy. The stimulation of signaling that can confer resistance suggests that combining autophagy or UPR inhibitors with antiestrogens would reduce the development of resistance in some breast cancers.

show abstract

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

Cited by 27 publications

References 90 publications

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Endocrine resistance in breast cancer – An overview and update

Knockdown of estrogen receptor‐α induces autophagy and inhibits antiestrogen‐mediated unfolded protein response activation, promoting ROS‐induced breast cancer cell death

Contact Info

Product

Resources

About