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.

乳房 X 光检测到的乳腺密度会影响乳腺癌的风险和进展，而纤维状胶原蛋白是乳腺密度的关键组成部分。然而，人们对影响乳房胶原蛋白生成的生理因素知之甚少。在雌性大鼠中，我们分析了整个怀孕、哺乳和断奶周期中表达最丰富的乳腺胶原蛋白和胶原蛋白相关蛋白的基因表达。我们确定了胶原蛋白基因调控的三相模式和生殖状态依赖性成分的证据。胶原蛋白沉积的初始阶段发生在怀孕期间，随后是哺乳期胶原蛋白抑制的活跃阶段。胶原调节的第三阶段发生在断奶诱导的乳腺退化期间，其特征是胶原沉积增加。Masson 的三色染色、二次谐波生成 (SHG) 成像和质谱法证实了胶原蛋白丰度的伴随变化。我们在从绝经前妇女获得的人乳腺组织中观察到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，与初产和泌乳腺体相比，退化大鼠乳腺具有更高的填充密度和更多的胶原纤维垂直于乳腺上皮细胞排列。退化的另一个特征是胶原交联酶赖氨酰氧化酶的高表达，这与交联胶原水平的增加有关。建议与乳腺癌相关，正如我们发现的那样，与在年龄匹配的未生育妇女中诊断出的乳腺癌相比，在最近产后妇女中诊断出的乳腺癌显示出与胶原蛋白沉积和交联增加一致的基因表达特征。使用公开可用的数据集，我们发现这种类似退化的胶原蛋白基因特征与整体乳腺癌患者和年轻女性的无进展生存期差相关​​。总之，正常乳腺中生理性胶原蛋白调节的这些发现可能有助于深入了解正常的乳房功能、乳房密度的病因，并告知乳腺癌的风险和结果。我们发现这种类似退化的胶原蛋白基因特征与整体乳腺癌患者和年轻女性的无进展生存期差相关​​。总之，正常乳腺中生理性胶原蛋白调节的这些发现可能有助于深入了解正常的乳房功能、乳房密度的病因，并告知乳腺癌的风险和结果。我们发现这种类似退化的胶原蛋白基因特征与整体乳腺癌患者和年轻女性的无进展生存期差相关​​。总之，正常乳腺中生理性胶原蛋白调节的这些发现可能有助于深入了解正常的乳房功能、乳房密度的病因，并告知乳腺癌的风险和结果。