Activation and clinical significance of the unfolded protein response in breast cancer

Scriven, Peter; Coulson, S.G.; Haines, R. Wheeler; Balasubramanian, Sabapathy P; Cross, Simon S.; Wyld, Lynda

doi:10.1038/sj.bjc.6605365

Cited by 133 publications

(121 citation statements)

References 24 publications

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“…Our group originally demonstrated that cell-surface GRP78 enables tumor targeting by circulating ligands in vivo (18,19), an observation confirmed by independent investigators (20,21). Both hormone receptor-positive and -negative breast cancers appear to overexpress GRP78 (22,23), and high levels of GRP78 in patients correlate to poor responses to chemotherapy and lower survival rates (24). However, despite its promise as a functional molecular target and as a potential prognostic marker in human breast cancer, the role of GRP78 in patients with IBC remains unclear, hence the impetus for this work.…”

mentioning

confidence: 75%

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Dobroff

D’Angelo

Eckhardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.inflammatory breast cancer | ligand-directed theranostics | molecular imaging | gene therapy | AAVP B reast cancer remains a major cause of cancer death in women (1), and one of its most lethal presentations is inflammatory breast carcinoma (IBC), a clinicopathological diagnosis characterized by diffuse erythema/edema involving the skin of the breast (a sign classically known as "peau d'orange") caused by tumor emboli within the dermal lymphatics. Although IBC comprises <5% of breast cancer cases, the tumor accounts for more than 10% of breast cancer mortality in the United States (2, 3). IBC is considered aggressive because it evolves rapidly-over days to weeks rather than months-with most patients presenting with lymph node involvement and more than 30% of patients having distant metastases at diagnosis (4, 5). Although IBC, like non-IBC breast cancers, is a heterogeneous disease and can occur as any of the five molecular subtypes, the IBC is most commonly ErbB2 overexpressing or triple negative (6), thus rendering a large armamentarium of targeted drugs ineffective. Finally, IBC generally presents with high-grade histology, elevated cell proliferation rate, and angiolymphatic invasion (5, 7). Indeed, the hallmark lymphatic invasion dictates the requirement for initial systemic treatment of IBC, because micrometastatic disease likely has occurred even in the Significance Inflammatory breast cancer (IBC) is defined clinically and pathologically. Dermal lymphatic invasion is typical but is neither necessary nor sufficient for diagnosis; sentinel lymph node biopsy is contraindicated, challenging multidisciplinar...

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mentioning

confidence: 75%

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Dobroff

D’Angelo

Eckhardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The UPR and its associated factors have been implicated in resistance to numerous cancer therapies (Pyrko et al 2007, Scriven et al 2009, Al-Rawashdeh et al 2010, Chen et al 2011. For example, increased expression of ATF4 is associated with decreased sensitivity to several therapies (Tanabe et al 2003, Igarashi et al 2007.…”

Section: Discussionmentioning

confidence: 99%

LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy

Nagelkerke¹,

Sieuwerts²,

Bussink³

et al. 2014

Endocrine-Related Cancer

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Lysosome-associated membrane protein 3 (LAMP3) is a member of the LAMP-family of proteins, which are involved in the process of autophagy. Autophagy is induced by tamoxifen in breast cancer cells and may contribute to tamoxifen resistance. In this study, the significance of LAMP3 for tamoxifen resistance in breast cancer was examined. The methods employed included use of clonogenic assays to assess the survival of MCF7 breast cancer cells with LAMP3 knockdown after tamoxifen treatment and of quantitative real-time PCR of LAMP3 to evaluate its predictive value for first-line tamoxifen treatment in patients with advanced breast cancer. Results show that tamoxifen treatment of MCF7 cells induced LAMP3 mRNA expression. LAMP3 knockdown in these cells increased tamoxifen sensitivity. Evaluation of expression of the autophagy markers, LC3B and p62, after LAMP3 knockdown showed increased expression levels, indicating that cells with LAMP3 knockdown have a suppressed ability to complete the autophagic process. In addition, knockdown of autophagy-associated genes resulted in sensitization to tamoxifen. Next, tamoxifen-resistant MCF7 cells were cultured. These cells had a sevenfold higher LAMP3 mRNA expression, showed elevated basal autophagy levels, and could be significantly resensitized to tamoxifen by LAMP3 knockdown. In patients treated with first-line tamoxifen for advanced disease (nZ304), high LAMP3 mRNA expression was associated with shorter progression-free survival (PZ0.003) and shorter post-relapse overall survival (PZ0.040), also in multivariate analysis. Together, these results indicate that LAMP3 contributes to tamoxifen resistance in breast cancer. Tamoxifen-resistant cells are resensitized to tamoxifen by the knockdown of LAMP3. Therefore, LAMP3 may be clinically relevant to countering tamoxifen resistance in breast cancer patients.

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“…These ER stress stimuli lead to the activation of the UPR pathway that can provide either pro-survival signals to reestablish cellular homeostasis or cell death signals if the stress is prolonged and unresolved (Scriven et al 2009;Li et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Identification of signaling pathways modulated by RHBDD2 in breast cancer cells: a link to the unfolded protein response

Lacunza

Rabassa

Canzoneri

et al. 2014

Cell Stress and Chaperones

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Rhomboid domain containing 2 (RHBDD2) was previously observed overexpressed and amplified in breast cancer samples. In order to identify biological pathways modulated by RHBDD2, gene expression profiles of RHBDD2 silenced breast cancer cells were analyzed using whole genome human microarray. Among the statistically significant overrepresented biological processes, we found protein metabolism-with the associated ontological terms folding , ubiquitination , and proteosomal degradation-cell death, cell cycle, and oxidative phosphorylation. In addition, we performed an in silico analysis searching for RHBDD2 co-expressed genes in several human tissues. Interestingly, the functional analysis of these genes showed similar results to those obtained with the microarray data, with negative regulation of protein metabolism and oxidative phosphorylation as the most enriched gene ontology terms. These data led us to hypothesize that RHBDD2 might be involved in endoplasmic reticulum (ER) stress response. Thus, we specifically analyzed the unfolding protein response (UPR) of the ER stress process. We used a lentivirus-based approach for stable silencing of RHBDD2 mRNA in the T47D breast cancer cell line, and we examined the transcriptional consequences on UPR genes as well as the phenotypic effects on migration and proliferation processes. By employing dithiothreitol as an UPR inducer, we observed that cells with silenced RHBDD2 showed increased expression of ATF6, IRE1, PERK, CRT, BiP, ATF4, and CHOP (p <0.01). We also observed that RHBDD2 silencing inhibited colony formation and decreased cell migration. Based on these studies, we hypothesize that RHBDD2 overexpression in breast cancer could represent an adaptive phenotype to the stressful tumor microenvironment by modulating the ER stress response.

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Activation and clinical significance of the unfolded protein response in breast cancer

Cited by 133 publications

References 24 publications

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy

Identification of signaling pathways modulated by RHBDD2 in breast cancer cells: a link to the unfolded protein response

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