Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

Costa, Ricardo; Santa-Maria, Cesar A.; Rossi, Giovanna; Carneiro, Benedito A.; Chae, Young Kwang; Gradishar, William J.; Giles, Francis J.; Cristofanilli, Massimo

doi:10.18632/oncotarget.13778

Cited by 24 publications

(21 citation statements)

References 120 publications

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“…Among all breast cancer types, inflammatory breast cancer (IBC) is a highly aggressive subtype characterized clinically by extremely motile tumor cell clusters that exhibit localized dermal invasion and frequent lymph node involvement (1-3). Despite an aggressive multimodal treatment regimen, tumor recurrence and metastatic progression are unmet challenges in IBC patients (4).…”

Section: Introductionmentioning

confidence: 99%

XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

et al. 2018

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Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intravital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular cross-talk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited. Signaling by the MNK kinase is essential in inflammatory breast cancer, and it can be targeted to inhibit XIAP-NFκB signaling and the aggressive phenotype of this malignancy. .

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Section: Introductionmentioning

confidence: 99%

XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

et al. 2018

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“…Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer; it accounts for 2–4% of breast cancer cases but causes 8–10% of breast cancer-related deaths in the United States [ 1 , 2 ]. IBC tumors have features associated with poor prognosis, such as overexpression of HER2, EGFR, E-cadherin, and nuclear factor κB [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer

et al. 2017

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Inflammatory breast cancer (IBC) is the most lethal and aggressive type of breast cancer, with a strong proclivity to metastasize, and IBC-specific targeted therapies have not yet been developed. Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in IBC. However, the mechanism behind the therapeutic effect of EGFR targeted therapy is not well defined. Here, we report that EGFR regulates the IBC cell population that expresses cancer stem-like cell (CSC) markers through COX-2, a key mediator of inflammation whose expression correlates with worse outcome in IBC. The COX-2 pathway promoted IBC cell migration and invasion and the CSC marker-bearing population in vitro, and the inhibition of this pathway reduced IBC tumor growth in vivo. Mechanistically, we identified Nodal, a member of the TGFβ superfamily, as a potential driver of COX-2-regulated invasive capacity and the CSC phenotype of IBC cells. Our data indicate that the EGFR pathway regulates the expression of COX-2, which in turn regulates the expression of Nodal and the activation of Nodal signaling. Together, our findings demonstrate a novel connection between the EGFR/COX-2/Nodal signaling axis and CSC regulation in IBC, which has potential implications for new combination approaches with EGFR targeted therapy for patients with IBC.

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“…Inflammatory breast cancer (IBC) is a rare, clinically and pathologically unique breast cancer subtype [ 1 ] that accounts for 2% to 6% of all breast cancers diagnosed in the United States [ 2 – 6 ] but 7% to 10% of all breast-cancer-related deaths [ 6 – 10 ]. It is the most aggressive subtype of breast cancer and associated with a poor prognosis [ 6 , 11 – 13 ], due in part to the high frequency of misdiagnosis at the onset of IBC [ 14 – 17 ] and its propensity to rapidly metastasize [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Some patients with IBC present without an underlying palpable mass [ 17 , 19 – 20 ]. The 5-year overall survival rate for patients with primary IBC is typically 62% to 68% [ 2 , 21 ]. In an attempt to improve this unfavorable outcome, the International Expert Panel on IBC proposed clinical guidelines important for the diagnosis of this disease [ 17 , 19 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Clinically relevant inflammatory breast cancer patient-derived xenograft–derived ex vivo model for evaluation of tumor-specific therapies

et al. 2018

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Inflammatory breast cancer (IBC) is a rare and aggressive presentation of invasive breast cancer with a 62% to 68% 5-year survival rate. It is the most lethal form of breast cancer, and early recognition and treatment is important for patient survival. Like non-inflammatory breast cancer, IBC comprises multiple subtypes, with the triple-negative subtype being overrepresented. Although the current multimodality treatment regime of anthracycline- and taxane-based neoadjuvant therapy, surgery, and radiotherapy has improved the outcome of patients with triple-negative IBC, overall survival continues to be worse than in patients with non-inflammatory locally advanced breast cancer. Translation of new therapies into the clinics to successfully treat IBC has been poor, in part because of the lack of in vitro preclinical models that can accurately predict the response of the original tumor to therapy. We report the generation of a preclinical IBC patient-derived xenograft (PDX)-derived ex vivo (PDXEx) model and show that it closely replicates the tissue architecture of the original PDX tumor harvested from mice. The gene expression profile of our IBC PDXEx model had a high degree of correlation to that of the original tumor. This suggests that the process of generating the PDXEx model did not significantly alter the molecular signature of the original tumor. We demonstrate a high degree of similarity in drug response profile between a PDX mouse model and our PDXEx model generated from the same original PDX tumor tissue and treated with the same panel of drugs, indicating that our PDXEx model had high predictive value in identifying effective tumor-specific therapies. Finally, we used our PDXEx model as a platform for a robotic-based high-throughput drug screen of a 386-drug anti-cancer compound library. The top candidates identified from this drug screen all demonstrated greater therapeutic efficacy than the standard-of-care drugs used in the clinic to treat triple-negative IBC, doxorubicin and paclitaxel. Our PDXEx model is simple, and we are confident that it can be incorporated into a PDX mouse system for use as a first-pass screening platform. This will permit the identification of effective tumor-specific therapies with high predictive value in a resource-, time-, and cost-efficient manner.

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Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

Cited by 24 publications

References 120 publications

XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype

EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer

Clinically relevant inflammatory breast cancer patient-derived xenograft–derived ex vivo model for evaluation of tumor-specific therapies

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