Syndecan-4 regulates the HER2-positive breast cancer cell proliferation cells via CK19/AKT signalling

Abstract

Despite the use of the highly specific anti-HER2 receptor (trastuzumab) therapy, HER2-positive breast cancers account for 20-30% of all breast cancer carcinomas, with HER2 status a challenge to treatment interventions. The heparan sulfate proteoglycans (HSPGs) are prominently expressed in the extracellular matrix (ECM), mediate breast cancer proliferation, development, and metastasis with most studies to date conducted in animal models. This study examined HSPGs in HER2-positive human breast cancer cell lines and their contribution to cancer cell proliferation. The study examined the cells following enhancement (via the addition of heparin) and knockdown (KD; using short interfering RNA, siRNA) of HSPG core proteins. The interaction of HSPG core proteins and AKT signalling molecules was examined to identify any influence of this signalling pathway on cancer cell proliferation. Our findings illustrated the HSPG syndecan-4 (SDC4) core protein significantly regulates cell proliferation with increased BC cell proliferation following heparin addition to cultures and decreased cell number following SDC4 KD. In addition, along with SDC4, significant changes in CK19/AKT signalling were identified as mediators of BC HER2-positive BC cell proliferation. This study provides evidence for a cell growth regulatory axis involving HSPGs/CK19 and AKT that represents a potential molecular target to prevent proliferation of HER2-positive breast cancer cells.

Keywords: AKT signalling; Breast cancer (BC); Cytokeratin (CK); Extracellular matrix (EMC); HER2-positive; Heparan sulfate proteoglycans (HSPGs); MDA-MB-453; SKBR3.