BS3-2: Mammary Stroma as an NSAID Target; Implications for Pregnancy-Associated Breast Cancer.
Authors: Schedin PJ , Lyons TR , O'Brien J , Callihan E , Russell T , Martinson H , Tan A-C , Hansen K , Keely PJ , Borges V 
Published: June 2012

Utilizing a young women's breast cancer cohort from the University of Colorado Cancer Center, we show that women diagnosed as late as five-ten years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy, and represent ∼50% of all young women's breast cancer patients. We propose that breast involution following pregnancy accounts for this poor prognosis. Characterization of involution identifies tissue remodeling programs that share similarities with microenvironments known to promote metastasis. Using SHG imaging, we find fibrillar collagen bundles with radially-aligned fibers similar to those observed in invasive tumors deposited in the involuting gland. By immunohistochemistry and FACS we find macrophages with an M2-polarization-like profile similar to tumor-associated macrophages at abundant levels during involution. In three independent mouse models for postpartum breast cancer, we isolate postpartum mammary gland involution as a driving force for cancer progression. Mammary tumors arising in the mouse involuting microenvironment express COX-2 and isolated tumor cells are motile and invasive in a collagen-1/COX-2 dependent manner. Targeting involution-macrophages as likely mediators of tumor promotion was accomplished using a previously described mouse transgenic model. Macrophage depletion during involution had catastrophic effects on normal mammary gland involution. Conversely, inhibition of COX-2 with celecoxib, aspirin or ibuprofen did not interfere with postpartum lobular regression. COX-2 inhibition did decrease tumor growth, local tumor cell dispersion and lung metastasis. NSAID treatment also suppressed collagen and tenascin-C deposition in the involuting microenvironment, suggesting that modulation of extracellular matrix proteins may be a novel mechanism by which NSAIDs exhibit chemopreventive activity. Our studies indicate two distinct roles for COX-2 in the postpartum setting. COX-2 activity within the tumor cell is required for invasiveness and COX-2 activity in the host promotes collagen fibrillogenesis. Several correlative observations implicate the collagen/COX-2 pathway in postpartum breast cancer in women: involuting breast tissue has increased collagen with radially aligned fibers, analysis of 11 publically available microarray data sets shows high COL1A and COX-2 independently correlate with decreased relapse free-survival in young breast cancer patients, and COX-2 protein is observed in DCIS lesions in postpartum cases at higher levels than nulliparous cases.

In summary, our studies suggest further research into COX-2 inhibitor use might provide a novel strategy to improve the prognosis of young women should they be diagnosed with postpartum breast cancer. The question of whether an NSAID based intervention study could be aimed at recently pregnant women at high risk for breast cancer also remains to be determined, but is an extremely desirable objective given that the ∼ 6 million pregnancies in the US per year.

Supported by grants from DoD Synergistic Idea Awards BC060531 & BC10400/001, Komen Foundation KG090629, DoD Idea Award BC074970 to PJK, ACS New England Division Postdoctoral Fellowship Spin Odyssey PF-08-257-01-CSM to TRL and DoD Predoctoral Grants BC073482 to JO and BC100910 to HM.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr BS3-2.