Background: Postpartum breast cancers, defined as breast cancers diagnosed within 5-10 years of last childbirth, are more than twice as likely to become metastatic and result in death. This devastating diagnosis affects thousands of young women annually. Our previous research revealed that non-invasive breast tumor cells become invasive and metastatic in postpartum mice compared to controls in nulliparous mice. We also revealed a novel feedback loop involving collagen mediated upregulation of COX-2, which mediates invasion and metastasis in postpartum mice. Subsequent gene expression analysis revealed a significant and specific upregulation of SEMA7A mRNA in postpartum breast tumor cells. The SEMA7A gene encodes for semaphorin 7a (Sema7a), a signaling molecule that drives neural development, immunity, and tissue remodeling in the lung. Our preliminary data demonstrate that silencing of SEMA7A cell line derived postpartum breast cancer xenografts delays growth, progression to invasive cancer, and reduces lymphangiogenesis in the tumor microenvironment. In addition, we have analyzed our young women’s breast cancer cohort to reveal that SEMA7A protein is significantly increased in postpartum patient tumors and in nulliparous patient tumors that subsequently recurred. Thus, we postulate that SEMA7A is also a general mediator of breast tumor progression. In support of this, our gene expression analysis of multiple human breast cancer datasets reveals that SEMA7A mRNA expression is associated with early recurrence, metastasis, and death. Cumulatively, these data support the hypothesis that SEMA7A promotes tumor progression in breast cancer patients and may be an important therapeutic target. Objective/Hypothesis: A collagen-mediated COX-2/SEMA7A signaling axis is key for invasion, stromal remodeling, and induction of vascular remodeling in the tumor microenvironment, all of which ultimately drive metastasis. Specific Aims: (1) Determine how collagen leads to upregulation of COX-2 and SEMA7A and whether targeting COX-2 in combination with silencing of SEMA7A will block tumor cell invasion. (2) Define the mechanisms by which SEMA7A promotes vascular remodeling and metastasis, determine whether targeting or co-targeting of SEMA7A and COX-2 will block metastasis, and define the relationship between SEMA7A and COX-2 in postpartum breast tumors. Cancer relevance: To establish clinical relevance, we will examine the relationship between SEMA7A and COX-2 protein expression, along with collagen and the vasculature, using multi-color immunostaining and correlate with invasion and recurrence in our postpartum breast cancer patient tissues. The expected outcomes are identification of mechanisms by which COX-2 and SEMA7A support breast tumor progression. Such results could positively impact thousands of breast cancer patients by defining new therapies targeted at the SEMA7A pathway. Given that SEMA7A expression is generally...