Mijic Sofija, Dabrosin Charlotta
Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
J Clin Endocrinol Metab. 2021 Jan 23;106(2):485-500. doi: 10.1210/clinem/dgaa820.
High mammographic density in postmenopausal women is an independent risk factor for breast cancer by undetermined mechanisms. No preventive therapy for this risk group is available. Activated platelets release growth factors that modulate the microenvironment into a protumorigenic state. Estrogens may affect the risk of breast cancer and platelet function. Whether platelets are activated in situ in breast cancer or in normal breast tissue at high risk of breast cancer and the association to estradiol remains elusive.
To investigate whether platelets are activated in situ in breast cancers and in dense breast tissue of postmenopausal women and explore correlations between estradiol, released platelet factors, and inflammatory proteins.
Sampling of in vivo proteins was performed using microdialysis in a total of 71 women: 10 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 premenopausal women.
Our data demonstrate increased levels of coagulation factors in dense breast tissue similar to that found in breast cancers, indicating excessive platelet activation. Premenopausal breasts exhibited similar levels of coagulation factors as postmenopausal dense breasts. Out of 13 coagulations factors that were upregulated in dense breasts, 5 exhibited significant correlations with estradiol, both locally in the breast and systemically. In breast tissue, positive correlations between coagulation factors and key inflammatory proteins and matrix metalloproteinases were detected.
Breast density, not estradiol, is the major determinant of local platelet activation. Inactivation of platelets may be a therapeutic strategy for cancer prevention in postmenopausal women with dense breasts.
绝经后女性乳腺钼靶密度高是乳腺癌的独立危险因素，但其机制尚不清楚。目前尚无针对该风险群体的预防性治疗方法。活化的血小板释放生长因子，可将微环境调节为促肿瘤状态。雌激素可能影响乳腺癌风险和血小板功能。血小板是否在乳腺癌原位或乳腺癌高风险的正常乳腺组织中被激活以及与雌二醇的关联仍不明确。
研究血小板是否在绝经后女性的乳腺癌和致密乳腺组织中原位被激活，并探讨雌二醇、释放的血小板因子和炎症蛋白之间的相关性。
使用微透析对总共71名女性进行体内蛋白质采样：10名乳腺癌患者、42名具有不同乳腺密度的绝经后健康女性和19名绝经前女性。
我们的数据表明，致密乳腺组织中凝血因子水平升高，与乳腺癌中发现的情况相似，表明血小板过度激活。绝经前乳房的凝血因子水平与绝经后致密乳房相似。在致密乳房中上调的13种凝血因子中，有5种在乳腺局部和全身均与雌二醇呈显著相关性。在乳腺组织中，检测到凝血因子与关键炎症蛋白和基质金属蛋白酶之间存在正相关。
乳腺密度而非雌二醇是局部血小板激活的主要决定因素。使血小板失活可能是预防绝经后乳腺致密女性患癌的一种治疗策略。
