Abstract A09: Advancements in understanding NSAID-based chemoprevention of postpartum breast cancer
Authors: Martinson Holly A. , Borakove Michelle , Jones Adriana , Borges Virginia F. , Schedin Pepper 
Published: May 2019

Abstract
Young women, within 5 years from last childbirth, have increased incidence of breast cancer as well as poorer prognosis compared to women who have never been pregnant. We refer to these breast cancers as postpartum. Our lab has proposed that the poor prognosis and possibly increased incidence of postpartum breast cancers are due to mammary gland remodeling following pregnancy, known as postpartum involution. Using rodent models and human breast tissue, characterization of postpartum involution has identified activated wound healing programs utilized to remodel the lactation competent gland back to a non-secretory state. For example, fibrillar collagen, matrix metalloproteinases, COX-2 expression, M2-like macrophages, T helper 2 (Th2)-associated cytokines IL-4, IL-13, TGF-β, and gene expression consistent with immune cell infiltrate are all increased within the mammary gland during postpartum involution. Here we report the pattern of immune cell influx into the postpartum murine mammary gland is very similar to that of classical wound healing, and importantly, we find infiltration of regulatory T cells and immunosuppressive IL-10+ macrophages that establish an immunosuppressive mammary microenvironment. Based on these studies, we have proposed that postpartum breast involution is a unique window of risk for breast cancer incidence and progression and may be an optimal target for chemoprevention.
Previously we have shown in an immune deficient model of postpartum breast cancer that NSAID therapy, restricted to postpartum involution, is sufficient to decrease tumor number, growth and metastasis to levels observed in nulliparous controls. However, given that we have found pro-tumorigenic immune modulation during postpartum involution, it becomes important to determine if NSAIDs are cancer-protective in an immune competent model. We report that immune competent Balb/c mice treated with ibuprofen during postpartum involution have decreased tumor growth due in part to reduced tumor cell proliferation and increased apoptosis. Since the tumor cells are COX-2 negative, the tumor suppressive effect of ibuprofen appears to be mediated through changes in the microenvironment. Consistent with a stromal mechanism, ibuprofen treated postpartum tumors had a decrease in total CD45 leukocytes, the ratio of cytokines IL-10/IL-12 was also decreased, and T cell presence was increased. These data suggest that ibuprofen is capable of improving T cell anti-tumor activity within the context of the immune suppressed microenvironment that is present during involution.
In summary, in the context of an immune competent, postpartum breast cancer model, ibuprofen decreases the tumor promotional attributes of the involution microenvironment. The question of how NSAIDs, classically considered to be immune suppressive, reverse the immune suppressive microenvironment of postpartum mammary cancers is under investigation. Potential relevance to chemoprevention in young women at high risk of developing postpartum breast cancer is evident; as ibuprofen is safe in the general population and further, treatment would be limited to the window of postpartum involution. However, caution is urged until the interactions of NSAIDs with the unique biology of the postpartum involving gland are more fully investigated.
Citation Format: Holly A. Martinson, Michelle Borakove, Adriana Jones, Virginia F. Borges, Pepper Schedin. Advancements in understanding NSAID-based chemoprevention of postpartum breast cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A09.