Elevated WBP2 Expression in HER2-positive Breast Cancers Correlates with Sensitivity to Trastuzumab-based Neoadjuvant Therapy: A Retrospective and Multicentric Study

Abstract

Purpose: Trastuzumab-based chemotherapy has shown remarkable clinical benefits for patients with HER2-positive breast cancer. However, treatment regimens involving trastuzumab had little or no effect for a subset of patients. Preliminary studies revealed WW-binding protein 2 (WBP2), an oncogenic transcription coactivator, to be coamplified with HER2 in 36% of HER2-positive breast cancers. We hypothesize that WBP2 regulates and correlates with the response of HER2-positive breast cancer to trastuzumab.Experimental Design: The coexpression of WBP2 and HER2 in breast tumors was validated using IHC. The role and mechanism of WBP2 in regulating breast cancer response to trastuzumab was elucidated using in vitro, patient-derived xenograft and murine xenograft models. A multicenter retrospective study involving 143 patients given neoadjuvant trastuzumab-based chemotherapy was conducted to determine whether WBP2 expression correlates with pathologic complete response (pCR).Results: Elevated expression of WBP2 significantly enhanced breast cancer's response to trastuzumab by augmenting trastuzumab-induced HER2 downregulation and cell-cycle arrest via inhibition of cyclin D expression. High level of WBP2 correlated with better pCR (67.19%) compared with low WBP2 level (26.58%). The highest response was observed in subgroups of patients with high WBP2-expressing tumors also aged below 50 years (77.78%) or were premenopausal in status (73.33%). Retrospectively, WBP2 demonstrated sensitivity of 80% to 81% and specificity of 76.5% to 80% in discriminating between patients showing pCR and non-pCR.Conclusions: WBP2 expression correlates with the response of HER2-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy.

The emerging roles of WBP2 oncogene in human cancers

“…A multicenter retrospective study revealed that breast cancer patients that were HER2 + and had high WBP2 expression responded significantly better to trastuzumab-based neoadjuvant therapy. This is most profound in patients <50 years old, who recorded a pathologic complete response of about 80% compared with 44.8% in HER2 + patients with no further stratifications [15].…”

“…Our latest study on WBP2 and HER2 expression in 296 resected breast tumor tissues revealed that the levels of WBP2 and HER2 were positively correlated [15]. HER2 + patients whose tumors showed high nuclear WBP2 expression (as determined by IHC) had the worst overall and disease-free survival than other groups.…”

“…WBP2 is not only a downstream substrate of EGFR/ HER2 signaling. It is also a potential predictive biomarker of response to trastuzumab-based neoadjuvant therapy in HER2 + breast cancer patients [15]. Exogenous WBP2 enhanced the inhibitory effect of trastuzumab on cell proliferation and cell cycle in vitro and in xenograft models.…”

Patient-Derived Xenograft Models of Breast Cancer and Their Application

“…They suggested that WBP2 would be useful as a companion diagnostic for the management of HER2 positive breast cancer with trastuzumab-based therapies. In addition, PDX models of HER2 positive breast cancer-derived brain metastases were also developed by Ni et al [71]. By using these PDX models, they found that the combined inhibition of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) led to the durable regression of metastasized tumors.…”

WBP2 Negatively Regulates Hippo Pathway By Competitively Binding To WWC3 With LATS1 To Promote The Malignant Phenotype Of Non-Small Cell Lung Cancer

“…Currently, a number of studies have focused on the molecular function of WBP2 in human solid tumors by assessing the impact of this protein on the biological phenotype of breast cancer. For example, in breast cancer, WBP2 is highly expressed and is signi cantly associated with poor prognosis [10,11]. WBP2 can bind to estrogen and progesterone receptors and can act as a co-activator of estrogen receptor (ER) and progesterone receptor (PR) hormone signaling transduction [12][13][14][15].…”