Guo Qiuchen, Sun Duanchen, Barrett Alexander S, Jindal Sonali, Pennock Nathan D, Conklin Matthew W, Xia Zheng, Mitchell Elizabeth, Samatham Ravikant, Mirza Naomi, Jacques Steven, Weinmann Sheila, Borges Virginia F, Hansen Kirk C, Schedin Pepper J
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University. Portland, OR 97239, USA.
Computational Biology Program, Oregon Health & Science University, Portland, OR 97239, USA.
Matrix Biol. 2022 Jan;105:104-126. doi: 10.1016/j.matbio.2021.10.006. Epub 2021 Nov 25.
Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.
乳腺钼靶检测到的乳腺密度会影响乳腺癌风险和进展，而纤维状胶原蛋白是乳腺密度的关键组成部分。然而，影响乳腺中胶原蛋白生成的生理因素却知之甚少。在雌性大鼠中，我们分析了在妊娠、哺乳和断奶周期中表达最为丰富的乳腺胶原蛋白及胶原蛋白相关蛋白的基因表达情况。我们确定了胶原蛋白基因调控的三相模式以及生殖状态依赖性组成的证据。胶原蛋白沉积的初始阶段发生在妊娠期，随后是哺乳期胶原蛋白抑制的活跃阶段。胶原蛋白调控的第三阶段发生在断奶诱导的乳腺退化过程中，其特征是胶原蛋白沉积增加。通过马松三色染色、二次谐波产生（SHG）成像和质谱法证实了胶原蛋白丰度的相应变化。我们在从绝经前女性获取的人类乳腺组织中观察到了类似的生殖状态依赖性胶原蛋白模式。SHG分析还揭示了整个生殖周期中胶原蛋白的结构变化，与未生育和哺乳期的腺体相比，退化期大鼠乳腺中胶原蛋白的堆积密度更高，且更多的胶原纤维垂直于乳腺上皮排列。退化期的另一个特征是胶原蛋白交联酶赖氨酰氧化酶的高表达，这与交联胶原蛋白水平的增加有关。我们发现，与年龄匹配的未生育女性所患乳腺癌相比，近期产后女性所患乳腺癌显示出与胶原蛋白沉积和交联增加相一致的基因表达特征，这表明其与乳腺癌具有相关性。利用公开数据集，我们发现这种类似退化的胶原蛋白基因特征与总体乳腺癌患者以及年轻女性患者较差的无进展生存期相关。总之，这些关于正常乳腺中生理胶原蛋白调控的发现可能为深入了解正常乳腺功能、乳腺密度的病因以及乳腺癌风险和预后提供线索。
