Physiological COX-2 Expression in Breast Epithelium Associates with COX-2 Levels in Ductal Carcinoma in Situ and Invasive Breast Cancer in Young Women

Abstract

Cyclooxygenase-2 (COX-2) overexpression is implicated in increased risk and poorer outcomes in breast cancer in young women. We investigated COX-2 regulation in normal premenopausal breast tissue and its relationship to malignancy in young women. Quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 96 premenopausal women with known clinical reproductive histories, and on rat mammary glands with distinct ovarian hormone exposures. COX-2 expression in the normal breast epithelium varied more than 40-fold between women and was associated with COX-2 expression levels in ductal carcinoma in situ and invasive cancer. Normal breast COX-2 expression was independent of known breast cancer prognostic indicators, including tumor stage and clinical subtype, indicating that factors regulating physiological COX-2 expression may be the primary drivers of COX-2 expression in breast cancer. Ovarian hormones, particularly at pregnancy levels, were identified as modulators of COX-2 in normal mammary epithelium. However, serial breast biopsy analysis in nonpregnant premenopausal women suggested relatively stable baseline levels of COX-2 expression, which persisted independent of menstrual cycling. These data provide impetus to investigate how baseline COX-2 expression is regulated in premenopausal breast tissue because COX-2 levels in normal breast epithelium may prove to be an indicator of breast cancer risk in young women, and predict the chemopreventive and therapeutic efficacy of COX-2 inhibitors in this population.

Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer

“…Animal procedures were approved with ethical consideration by the University of Colorado Anschutz Medical Campus Institutional Animal Care and Use Committee. For the tumor models, 200,000 DCIS-GFP (xenograft), 20,000 D2A1 (isograft), or 200,000 66cl4-LUC (isograft) cells were COX-2 is upregulated in mammary epithelial cells during involution (40), and here, we show that prolymphangiogenic growth factors VEGF-C and VEGF-D were similarly upregulated. Given that COX-2 has been shown to regulate both VEGF-C and VEGF-D (18,41), the possibility that COX-2 also promotes lymphangiogenesis in the breast via regulation of VEGF-C and VEGF-D cannot be ruled out by the results presented herein.…”

Physiologically activated mammary fibroblasts promote postpartum mammary cancer

“…Surprisingly, mammary epithelial cells (MECs) express high levels of COX2 during weaning-induced involution and MECs may be the dominant source of PGE2 in the mammary gland (66). Supportive roles for MECs in fibroblast activation and collagen production have been previously reported.…”

New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis

“…In several breast cancer studies examining COX-2 expression (mRNA and/or protein by immunohistochemistry), COX-2 was only expressed in tumor, not normal breast tissue, and overall its expression in tumors predicted a worse prognosis [59][60][61][62][63][64][65][66][67]. COX-2 expression was used to predict whether tumors were likely to metastasize or, in the case of ductal carcinoma in situ (DCIS), to recur.…”