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Wessells, V.

Publications and source records attributed to Wessells, V..

2 recordsLinked to original sources
bioRxiv2025

Targeting Semaphorin 7a signaling in preclinical models of estrogen receptor-positive breast cancer

Estrogen receptor-positive (ER+) breast cancer (BC) comprises over 70% of breast cancers and is the leading cause of BC-related deaths in women worldwide. Despite available therapies targeting ER in BC, recurrence occurs in many patients due to therapeutic resistance. Semaphorin 7a (SEMA7A) is a biomarker associated with poor prognosis and endocrine therapy resistance for BC patients. Survival analyses of ER+ BC patients on endocrine therapy confirm early recurrence in patients with SEMA7A+ tumors. Thus, we aim to establish novel treatment strategies to improve outcomes for patients with ER+ SEMA7A+ BC. In this paper we investigate the mechanisms by which SEMA7A promotes resistance to endocrine therapy and its potential as a therapeutic target for ER+ BC. Our studies suggest that SEMA7A binds to integrins {beta}1 and {beta}4 and activates AKT mediated pro-survival signaling via its RGD domain. Using syngeneic ER+ models, tumors in were treated with PI3K inhibitors (20mg/kg alpelisib; 10mg/kg GCT-007), alone or in combination with tamoxifen (0.5 mg/100uL peanut oil), which resulted in decreased tumor growth. Tumors were also treated with a combination of an anti-SEMA7A antibody (SmAbH1) (100-250mg/kg) and fulvestrant (83mg/kg), compared to single agents. Our results demonstrate that direct inhibition of SEMA7A via SmAbH1 significantly reduces tumor growth of SEMA7A+ tumors, and the combination with fulvestrant may be even more effective. Our studies suggest that patients with ER+SEMA7A+ tumors should be candidates for PI3K-targeted therapies or anti-SEMA7A-based therapy. TRANSLATIONAL RELEVANCEOur studies propose inhibition of a novel target in estrogen receptor-positive (ER+) breast cancer (BC) with an anti-Semaphorin 7a (SEMA7A) monoclonal antibody (SmAbH1). We show efficacy of SmAbH1 as a single agent and in combination with endocrine therapy in preclinical models. We also show that targeting of SEMA7A signaling, including the use of well-known and novel PI3K inhibitors, could be an effective treatment strategy for patients with SEMA7A+ BC, particularly in combination with standard of care. Our mechanistic studies detail the cellular signaling pathway activated by SEMA7A and support the further investigation of these novel drug combinations for clinical use. Further, SEMA7A is a biomarker for poor prognosis and decreased patient survival, posing the need for a clinical diagnostic test for SEMA7A levels in BC patients, which we are currently developing. O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/655360v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@18f3790org.highwire.dtl.DTLVardef@188cfbcorg.highwire.dtl.DTLVardef@fe71aaorg.highwire.dtl.DTLVardef@d87f98_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2019

Cross-talk between SIM2s and NFkB regulates cyclooxygenase 2 expression in breast cancer

BackgroundBreast cancer is a leading cause of cancer-related death for women in the United States. Thus, there a need to investigate novel prognostic markers and therapeutic strategies. Inflammation raises challenges to both treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFkB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, the gene that encodes for cyclooxygenase 2 (COX-2), which is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in inflammation. Here we investigate the effect of Singleminded 2s, a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFkB and COX-2.\n\nMethodsWe utilized in vitro reporter assays, immunoblot analyses, qPCR and immunohistochemical analysis to dissect the relationship between NF{kappa}B, SIM2s, and COX-2. Furthermore, we utilized COX-2 targeting strategies to determine tumor suppressive activities.\n\nResultsOur results reveal that SIM2s attenuates the activation of a NF{kappa}B via luciferase reporter assays. Furthermore, immunostaining of lysates from breast cancer cells over expressing SIM2s showed reduction in various NF{kappa}B signaling proteins, whereas knockdown of SIM2 revealed increases in the same NF{kappa}B signaling proteins. Additionally, by increasing NF{kappa}B translocation to the nucleus in DCIS.COM cells, we show that NF{kappa}B signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NF{kappa}B translocation in DCIS.COM cells increases SIM2s expression. We also found that NF{kappa}B/p65 represses SIM2 in via dose-dependent manner and when NF{kappa}B is suppressed the effect on the SIM2 is negated. Additionally, our CHIP analysis confirms that NF{kappa}B/p65 binds directly to SIM2 promoter site and that the NF{kappa}B sites in the SIM2 promoter are required for NFkB-mediated suppression of SIM2s. Finally, over expression of SIM2s decreases PTGS2 in vitro and COX-2 staining in vivo while decreasing PTGS2 and/or Cox-2 activity results in re-expression of SIM2. Our findings identify a novel role for SIM2s in NF{kappa}B signaling and COX-2 expression.\n\nConclusionsThese findings provide evidence for a mechanism where SIM2s may represses COX-2 expression to provide an overall better prognosis for breast cancer patients.

cancer biology↗