CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells

Abstract

Trastuzumab is widely used in the clinical treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer, but the patient response rate is low. CD147 stimulates cancer cell proliferation, migration, metastasis and differentiation and is involved in chemoresistance in many types of cancer cells. Whether CD147 alters the effect of trastuzumab on HER2-positive breast cancer cells has not been previously reported. Our study confirmed that CD147 suppression enhances the effects of trastuzumab both in vitro and in vivo. CD147 suppression increased the inhibitory rate of trastuzumab and cell apoptosis in SKBR3, BT474, HCC1954 and MDA-MB453 cells compared with the controls. Furthermore, CD147 knockdown increased expression of cleaved Caspase-3/9 and poly (ADP-ribose) polymerase (PARP) and decreased both mitogen-activated protein kinase (MAPK) and Akt phosphorylation in the four cell lines. In an HCC1954 xenograft model, trastuzumab achieved greater suppression of tumor growth in the CD147-knockdown group than in the shRNA negative control (NC) group. These data indicated that enhancement of the effect of trastuzumab on HER2-positive cells following CD147 knockdown might be attributed to increased apoptosis and decreased phosphorylation of signaling proteins. CD147 may be a key protein for enhancing the clinical efficacy of trastuzumab.

Plasma soluble cluster of differentiation 147 levels are increased in breast cancer patients and associated with lymph node metastasis and chemoresistance

“…In a recent study, CD147 knockdown was shown to improve the antitumour efficacy of trastuzumab in HER2-positive breast cancer cells. 35 Although we found that plasma sCD147 levels were significantly higher in the HER2-positive breast cancer subtype than in luminal A, luminal B, and TNBC subtypes, plasma sCD147 had no association with expression of HER2 or oestrogen/progesterone receptors in breast cancer. The reason for this finding is that there are four breast cancer subtypes-luminal A, luminal B, HER2-positive, and TNBC-according to oestrogen/ progesterone receptor, HER2, and Ki67 status.…”

Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer

“…1d ) whereas HCC1954 cells were resistant (Fig. 1c ) to trastuzumab treatment in vitro , which are in agreement with published studies by other group 30 , 31 . However, trastuzumab was quite effective in inhibiting the growth of HCC1954 tumor in our xenograft model (Fig.…”

“…The unique xenograft model, HCC1954 injected into the flank of BALB/c- nu/nu mice, used in our study might be account for this discrepancy. In studies with reported trastuzumab resistance by the HCC1954 models, different strains of immune deficient host mice were used, which include nu/nu: Alpk 32 and CB17 SCID-beige 33 mice, or HCC1954 cells were injected into different location (i.e mammary fat pad) in the host mice 31 , 33 . In any event, because the efficacy of Enza in inhibiting HCC1954 cell growth in vitro and in vivo , our data suggest that Enza may be used to overcome trastuzumab resistance.…”

The molecular mechanisms of chemoresistance in cancers

“…In HCC, CD147 overexpression initiated a TGF-β signaling cascade, including Slug expression, cadherin switching, and morphological EMT changes [ 89 ]. Xiong et al [ 90 ] confirmed that CD147 suppression enhanced the effects of trastuzumab of HCC cells by up-regulating the cleavage of Caspase-3/9 and PARP, and down-regulating MAPK and Akt phosphorylation.…”