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Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2 | Nature Medicine
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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.
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nature portfolio permissions reprints privacy policy nature medicine reviewers advertising her2/neu-induced mammary tumorigenesis social media nature 420 nature 436 nature 459 nature cancer research registry-based cohort study study stromal-epithelial interactions /neu-induced breast cancer weaning-induced breast involution hypothesis development dana-farber cancer institute research nonsteroidal anti-inflammatory drugs estrogen receptor-negative cancers springerlink instant access author correspondence involuting mammary gland permissions jenean o'brien breast cancer metastasis mouse mammary gland matrix metalloproteinase expression negative prognostic factor mammary gland biology measuring breast density mammary gland biol amc cancer fund defense award bc074970 tumor cell infiltration breast carcinomas arising human breast carcinoma human dcis studies mammary ecm composition postpartum breast cancer prospective cohort study enhancing integrin signaling privacy data support systemic stromal effects pepper schedin mammary microenvironment gene expression patterns subsequent tumor events
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