Biology subjects

Lyons, T. R.

Publications and source records attributed to Lyons, T. R..

3 recordsLinked to original sources

bioRxiv2019

Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance

Approximately 70% of all breast cancers are estrogen receptor positive (ER+BC) and endocrine therapy has improved survival for patients with ER+BC. Yet, up to half of these tumors recur within 20 years. Recurrent ER+BCs develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER+BC. We found that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER+BC. We show that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with anti-estrogen treatments. Additionally, overexpression of SEMA7A in ER+ cell lines drives increased in vitro growth in the presence of estrogen-deprivation, tamoxifen, and fulvestrant. In in vivo studies, we found that SEMA7A confers primary tumor resistance to fulvestrant and, importantly, induced lung metastases. Finally, we identify pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors and propose that targeting with inhibitors of survival signaling such as venetoclax may have efficacy for treating SEMA7A+ tumors. SIGNIFICANCEWe report that SEMA7A predicts for, and likely contributes to, poor response to standard-of-care therapies and suggest that patients with SEMA7A+ER+ tumors may benefit from alternative therapeutic strategies.

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↗

bioRxiv2019

Semaphorin 7a dependent programs of cell surivival, matrix remodeling, and EMT drive postpartum breast tumor progression

Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. Additionally, women within 10 years of most recent childbirth at diagnosis are [~]3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis, all of which are also increased in pre-clinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in a model of PPBC while overexpression is sufficient to increase growth in nulliparous hosts. Further, we show that SEMA7A promotes multiple known drivers of PPBC progression including tumor associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment. Additionally, we show for the first time that SEMA7A expressing cells deposit fibronectin to promote tumor cell survival. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression and that targeting SEMA7A may open avenues for novel therapeutic strategies.

cancer biology↗