Abstract B61: Postpartum mammary gland involution drives DCIS progression through collagen and COX-2, identifying a target for intervention

Abstract

Abstract Prognosis of young women's breast cancer is influenced by reproductive history. Women diagnosed within five years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. We propose that breast involution following pregnancy accounts for the poor prognosis of breast cancers diagnosed postpartum. Our ‘involution hypothesis’ states that the physiologically normal microenvironment of the postpartum involuting gland is tumor promotional; however, testing the involution hypothesis has been limited by lack of pre-clinical models. We developed a mouse xenograft model of PABC that isolates postpartum mammary gland involution as a driving force for breast cancer progression and metastasis. In this model, human breast cancer cells are injected into actively involuting mouse mammary glands and nulliparous controls. Results from this model indicate that tumor cells exposed to the collagen rich involuting mammary microenvironment form larger tumors characterized by abundant fibrillar collagen, high COX-2 expression, and an invasive phenotype. In culture, these tumor cells are invasive in a collagen/COX-2-dependent manner. Importantly, in the involuting mammary gland, inhibition of COX-2 with celecoxib or ibuprofen reduced the collagen fibrillogenesis associated with involution, as well as tumor growth and lung infiltration. These anti-tumor effects were observed without blocking apoptosis of secretory mammary epithelial cells, which is required to remodel the gland to a non-secretory state, and is a requisite for advancing this strategy to clinical trial. The question of whether an NSAID based intervention study could be aimed at recently pregnant women at high risk for breast cancer remains to be determined, but is an extremely desirable objective given that there are more than 6 million pregnancies in the US per year. In summary, these data support further research to determine whether women at high-risk for postpartum breast cancer would benefit from treatment with NSAIDs during postpartum involution. This work was funded by DOD, Komen, and ACS. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B61.