Elevated serum HER‐2 predicts poor prognosis in breast cancer and is correlated to ADAM10 expression

Abstract

Human epidermal growth factor receptor‐2 (HER‐2) overexpression in breast tumor tissues is associated with a poor prognosis but may benefit from treatment with trastuzumab. The extracellular domain (ECD) of HER‐2 can be measured in serum and which has been a new inspection item in clinical laboratory of several hospitals. However, whether serum HER‐2 ECD can be a marker of HER‐2 status in tumor tissues still confused clinicians. This study is a retrospective observation to explore the correlation between serum HER‐2 ECD shedding and tissue HER‐2 status in breast cancer patients. Meanwhile, we will further uncover the potential clinical significance of serum HER‐2 ECD detection. A total of 545 unselected breast cancer patients from Fudan University Shanghai Cancer Center were enrolled in this study. At primary diagnosis without any treatment, serum HER‐2 ECD was measured on ADVIA Centaur assay; meanwhile, tissue HER‐2 from core needle biopsy was tested through immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). We showed that serum HER‐2 ECD concentration was related to tissue HER‐2 status. Nevertheless, 36.9% of patients with tissue HER‐2 overexpression had low levels of HER‐2 ECD shedding (<15 ng/mL) in serum. Here, we demonstrated that HER‐2 ECD shedding was also associated with protein expression and alpha‐secretase activity of a disintegrin and metalloproteinase 10 (ADAM10) using tumor tissues and cell lines. Progression‐free survival (PFS) data from breast cancer patients in TNM phase II and III with tissue HER‐2 IHC 3+ were analyzed using Kaplan‐Meier plotter. The patients with serum HER‐2 ECD above 15 ng/mL had lower progression‐free survival than those with serum HER‐2 ECD <15 ng/mL. Thus, serum HER‐2 ECD could be a biomarker to identify the subgroup of poorer outcome among HER‐2 overexpression breast cancer patients. Inhibition of ADAM10 activity may have potential therapeutic benefit for this most aggressive tumor subgroup.

Primary Research ADAM10 is involved in the oncogenic process and chemo-resistance of triple-negative breast cancer via regulating Notch1 signaling pathway, CD44 and PrPc

“…It has also been implicated in the pathogenesis of several types of human malignant tumors including breast cancer [36]. But the roles of ADAM10 in breast cancer have been focused on the HER2 positive type [20][21][22][23] rather than on the triple-negative type [25,37]. Here, we have demonstrated that the higher level of ADAM10 in its active form is expressed not only in HER2 ampli ed cell line SK-BR-3 but also in TNBC cell lines MDA-MB-231, MDA-MB-468 and BT-549, compared with ER positive cell line MCF7.…”

“…Additionally, ADAM10 contributes to HER receptor activation by shedding of HER ligands such as betacellulin and mediates Trastuzumab treatment resistance [21]. Zheng et al has also demonstrated that HER2 extracellular domain (ECD) shedding is asscociated with α-secretase activity of ADAM10 in breast cancer tissues and cell lines [22]. MEL-18 depletion induced trastuzumab resistance by increasing ADAM10/17 mediated ErbB ligand production and receptor heterodimerization in HER2 positive breast cancer [23].…”

ADAM10 is involved in the oncogenic process and chemo-resistance of triple-negative breast cancer via regulating Notch1 signaling pathway, CD44 and PrPc

“…It has also been implicated in the pathogenesis of several types of human malignant tumors including breast cancer [36]. However, the studies on the roles of ADAM10 in breast cancer have only focused on the HER2 positive type [20][21][22][23] rather than on the triplenegative type [25,37]. Here, we have demonstrated that the higher level of ADAM10 in its active form is expressed not only in HER2 ampli ed cell line SK-BR-3 but also in TNBC cell lines MDA-MB-231, MDA-MB-468 and BT-549, compared with ER positive cell line MCF7.…”

Targeting ADAM10 in Cancer and Autoimmunity

“…Increased shedding of HER2 into a soluble form, HER2-extra cellular domain (ECD) by ADAM10 has recently been shown to be predictive of reduced progressionfree survival (74). In 545 HER2 positive invasive ductal mammary carcinoma (NST) patients, it was found that a high serum HER2-ECD relative to tumor HER2 level was predictive of reduced progression-free survival (74). Feldinger et al demonstrated that after treatment with trastuzumab, ADAM10 levels increased both in vitro and in vivo using PDX (75).…”