Abstract PR10: Silencing of semaphorin 7a attenuates breast tumor progression
Authors: Sarah Black, Andrew Nelson, Natalia Gurule, Bernard Futscher, Traci Lyons
Journal: Cancer Research (2016)

Abstract Determining what drives conversion of non-lethal to lethal breast cancers is of utmost importance for understanding and blocking tumor metastasis. We have identified semaphorin 7a (Sem7a) as a potent driver of human breast cancer progression, suggesting it may represent a novel target to inhibit metastasis. Sem7a is a GPI membrane anchored protein that promotes attachment and spreading in multiple cell types1,2; previous reports have identified a role for Sem7a in mouse mammary tumorigenesis, including promotion of tumor growth and EMT, as well as induction of angiogenic cytokine production by macrophages and metastatic outgrowth in the lung3-5. However, Sem7a has not been investigated in human breast tumors, so we utilized publicly available microarray datasets and found that SEMA7A gene expression is increased in ~45% of all breast cancers. Further, we found SEMA7A upregulation was associated with poor prognosis, which is consistent with a role in metastasis. Specifically, breast cancer patients with high expression of SEMA7A are at risk for early recurrence and have decreased overall and distant metastasis-free survival rates. We used in vitro and in vivo approaches to assess the role of SEM7a in human breast tumor progression. In vivo, we show that shRNA mediated silencing of Sem7a significantly slows tumor growth, delays tumor progression from in situ to locally invasive disease, and decreases tumor associated lymphangiogenesis. Furthermore, having previously shown that collagen I and COX-2 drive tumor progression in our breast cancer models6,7, we identified a relationship between COX-2 and Sem7a expression at the mRNA and protein levels. Finally, using three- dimensional spheroid and tube formation assays, we show that semaphorin 7a promotes tumor cell invasion on collagen, and lymphangiogenesis, via activation of the β1-integrin receptor. Our results indicate that Sem7a may be novel target for blocking multiple aspects of breast tumor progression that lead to metastasis. References: 1. Pasterkamp, R.J., Peschon, J.J., Spriggs, M.K. &amp; Kolodkin, A.L. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424, 398-405 (2003). 2. Scott, G.A., McClelland, L.A. &amp; Fricke, A.F. Semaphorin 7a promotes spreading and dendricity in human melanocytes through beta1-integrins. The Journal of investigative dermatology 128, 151-161 (2008). 3. Allegra, M., et al. Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells. Molecular biology of the cell 23, 3873-3881 (2012). 4. Garcia-Areas, R., et al. Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice. Frontiers in physiology 5, 17 (2014). 5. Ma, B., et al. Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis. Cancer research 75, 487-496 (2015). 6. Lyons, T.R., et al. Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer. The Journal of clinical investigation (2014). 7. Lyons, T.R., et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nature medicine 17, 1109-1115 (2011). Citation Format: Sarah Black, Andrew Nelson, Natalia Gurule, Bernard Futscher, Traci Lyons. Silencing of semaphorin 7a attenuates breast tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr PR10.