Abstract CN10-03: Stromal signals from the involuting microenvironment that are important in postpartum breast cancer

Abstract

Abstract Prognosis of young women's breast cancer is influenced by pregnancy. Women diagnosed within 5 years of childbirth have worse prognosis than age-matched nulliparous women or women diagnosed while pregnant. These data indicate that pregnancy-associated breast cancer (PABC) exists as two subtypes, with poor prognosis associated with cases diagnosed in the postpartum setting rather than during pregnancy. We propose that breast involution following pregnancy accounts for the poor prognosis of breast cancers diagnosed within 5 years of childbirth. Characterization of the involuting mammary gland has identified tissue remodeling programs associated with wound healing and inflammatory responses that share similarities with cancer microenvironments known to be tumor promotional. Based on these results, we proposed the Involution Hypothesis, which states that the physiologically normal microenvironment of the postpartum involuting gland is tumor promotional. We estimate a high proportion of young women with breast cancer actually have a “recent” pregnancy as a negative prognostic feature. Specifically, with an upper limit of 40 years of age for reproductive potential and a recent pregnancy defined as within 5 years of diagnosis, an estimated 20,000 cases of breast cancer per year in the U.S. may qualify as postpartum. Targeting the postpartum window with interventions designed to reduce the tumor promotional attributes of involution is highly attractive, as this window of risk is restricted in time and the population is readily identifiable. Testing the Involution Hypothesis has been limited by lack of preclinical models. We describe here 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 mammary MCFDCIS.com tumor cells injected into the postpartum, involuting mammary gland form more proliferative and invasive tumors than tumor cells injected into the nulliparous gland. The involuting gland is characterized by high levels of radiating collagen fibers organized similar to collagen associated with invasive tumors across species. In our model of postpartum breast cancer, fibrillar collagen is identified as a primary mediator of tumor progression. Mammary tumors arising in the collagen-rich, involuting microenvironment are invasive and have increased levels of COX-2. In vitro, primary tumor cells isolated from PABC tumors are motile and invasive in a COX-2 dependent manner. Evidence that COX-2 induced motility is dependent on collagen signaling is demonstrated with functional blocking antibodies against β1-integrin, 2β1-integrin, and integrin associated protein CD47. These data suggest that treatment targeting COX-2 during postpartum involution may decrease progression of postpartum breast cancer. To test this hypothesis, mice were treated with the NSAID ibuprofen for two weeks coinciding with postpartum mammary gland involution. NSAID treatment was found to reduce tumor size, COX-2 expression, and lung cell seeding in this model. These antitumor effects were observed without blocking apoptosis of secretory mammary epithelial cells, which is required to remodel the gland to a nonsecretory 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 U.S. per year. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN10-03.