Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2

• Published in: Nature medicine Vol. 17; no. 9; pp. 1109 - 1115
• Main Authors: Lyons, Traci R, O'Brien, Jenean, Borges, Virginia F, Conklin, Matthew W, Keely, Patricia J, Eliceiri, Kevin W, Marusyk, Andriy, Tan, Aik-Choon, Schedin, Pepper
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2011; Nature Publishing Group
• Subjects: 631/67/1059; 631/67/322; 692/699/67/1347; 692/700/1750; Analysis of Variance; Animals; Anti-inflammatory agents; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - physiopathology; Cancer Research; Carcinoma, Ductal; Carcinoma, Ductal - drug therapy; Carcinoma, Ductal - physiopathology; Celecoxib; Cell Line, Tumor; Cellular biology; Cyclooxygenase 2 - metabolism; Cyclooxygenases; Development and progression; Disease Models, Animal; Female; Fibrillar Collagens - metabolism; Gene expression; Genetic aspects; Humans; Ibuprofen - pharmacology; Ibuprofen - therapeutic use; Immunohistochemistry; In Situ Hybridization, Fluorescence; Infectious Diseases; Infiltration; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - physiology; Metabolic Diseases; Mice; Mice, SCID; Molecular Medicine; Neoplasm Invasiveness - physiopathology; Neurosciences; Nonsteroidal anti-inflammatory drugs; Physiological aspects; Postpartum period; Postpartum Period - drug effects; Postpartum Period - physiology; Pregnancy; Proteins; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Tumors; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2416

Postpartum involution of the mammary gland is a recognized risk factor for breast cancer. This report identifies a mechanism that could be at least partially responsible for the increased risk, involving both the elevated expression of COX-2 and its interaction with extracellular collagen, the deposition of which occurs during postpartum involution. Both these factors promote tumor growth and invasion in mice and correlate with poor prognosis in young women with breast cancer. The data suggest that ibuprofen treatment during involution is a safe and effective approach to diminish pregnancy-associated cancer. The prognosis of breast cancer in young women is influenced by reproductive history. Women diagnosed within 5 years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors that are characterized by abundant fibrillar collagen, high cyclooxygenase-2 (COX-2) expression and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2–dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high risk for postpartum breast cancer would benefit from treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) during postpartum involution.