Abstract
Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.
Highlights
Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by negative expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of the human epidermal growth factor receptor 2 (HER2) [1]
Given that post-transcriptional regulation often leads to generally low correlation between mRNA and protein concentrations [23] the results we obtained for BCL2- associated athanogene 3 (BAG3) mRNA and BAG3 protein expression levels in the TNBC cell line panel were positive with six cell lines showing a similar trend
High BAG3 expression has previously been associated with a worse prognosis and poorer survival in aggressive cancers such as pancreatic adenocarcinoma [16] medullablastoma [26] and metastatic melanoma [27]
Summary
Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by negative expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of the human epidermal growth factor receptor 2 (HER2) [1]. TNBC patients can exhibit poor prognosis and high relapse rates at early stages after adjuvant and neoadjuvant chemotherapy treatment [2, 3]. The epidermal growth factor receptor (EGFR) is known to be over expressed in >50% of TNBC patients [4]. Inhibiting EGFR alone in TNBC has had limited efficacy [5], possibly due to the presence of additional mutations in downstream EGFR signaling nodes such as KRAS and PTEN. Combination therapies targeting www.oncotarget.com multiple signalling nodes have proved more successful than single target therapies [6, 7]
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