Abstract
Simple SummarySpecific drug targets for breast ductal carcinoma in situ (DCIS) remain elusive, despite increasing disease prevalence and burden to healthcare services. Estrogen receptor (ER)-negative HER2-positive DCIS, associated with the poorest patient prognosis, is in particular need of novel therapeutic avenues. This report provides the first evidence that a cell surface protein called JAM-A is upregulated on human DCIS patient tissues and can be readily targeted by a novel JAM-A-binding peptide inhibitor in separate in vivo models of DCIS. The anti-tumor efficacy and lack of systemic toxicity of this lead inhibitor, coupled with early indications of potential signaling pathways implicated, support the value of future studies investigating JAM-A as a novel drug target in DCIS patients.Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS.
Highlights
Ductal carcinoma in situ (DCIS) is a pre-invasive form of breast cancer in which tumors are histologically confined to milk ducts without locally invading past the myoepithelial layer encircling the ductal epithelium, making them surgically resectable with high success rates [1]
With evidence that high expression of the adhesion protein JAM-A marks aggressive disease in patients with invasive breast ductal carcinoma [8–12], this study set out to determine if JAM-A expression was elevated at the earlier phase of ductal carcinoma in situ (DCIS)
Evidence that JAM-A may regulate human epidermal growth factor receptor-2 (HER2) expression [8] and that HER2 expression is proportionally higher in DCIS than invasive ductal carcinomas [30] or flags DCIS tumors that progress to invasive disease [14], the aim of this study was to explore the value of pharmacologically inhibiting JAM-A in HER2-positive breast DCIS models
Summary
Ductal carcinoma in situ (DCIS) is a pre-invasive form of breast cancer in which tumors are histologically confined to milk ducts without locally invading past the myoepithelial layer encircling the ductal epithelium, making them surgically resectable with high success rates [1]. 20% of breast cancer patients present with DCIS, frequently diagnosed via screening mammography. Genomic and phenotypic similarities have suggested DCIS as a precursor of invasive ductal carcinoma [3]; multi-decade follow-up studies of DCIS patients whose only interventions were surgical biopsies have estimated that
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