胶原蛋白在调节乳腺癌进展和治疗耐药性方面发挥着关键作用。更好地了解肿瘤允许性和限制性胶原基质的特征和驱动因素对于改善预后和开发更有效的治疗策略至关重要。在这项研究中，我们结合体外、体内和生物信息学实验，证明 III 型胶原蛋白 (Col3) 在人类乳腺癌中发挥肿瘤限制作用。我们证明，Col3 缺陷的人类成纤维细胞产生肿瘤允许的胶原蛋白基质，在非侵入性和侵入性乳腺癌细胞系中驱动细胞增殖并抑制细胞凋亡。在人类三阴性乳腺癌活检样本中，我们证明，与侵入性区域相比，非侵入性区域中 Col3 相对于 I 型胶原蛋白 (Col1) 的沉积量有所增加。同样，对来自癌症基因组图谱 BRCA 队列的 1000 多名乳腺癌患者活检进行的生物信息学分析显示，与具有较高 Col1:Col3 的患者相比，具有较高 Col3:Col1 大量肿瘤表达的患者的总体生存率、无病生存率和无进展生存率有所改善表达。使用已建立的 3D 培养模型，我们发现 Col3 可以增加球状体的形成，并诱导类似于非肿瘤性乳腺腺泡的管腔样结构的形成。最后，我们的体内研究表明，与对照组相比，将鼠乳腺癌细胞 (4T1) 与补充 rhCol3 的水凝胶共注射可限制肿瘤生长并减少肺部转移负担。总而言之，这些数据共同支持 Col3 在人类乳腺癌中的肿瘤抑制作用，并表明增加 Col3 的策略可能提供安全有效的治疗方式来限制乳腺癌患者的复发。© 2024。作者。

Collagen plays a critical role in regulating breast cancer progression and therapeutic resistance. An improved understanding of both the features and drivers of tumor-permissive and -restrictive collagen matrices are critical to improve prognostication and develop more effective therapeutic strategies. In this study, using a combination of in vitro, in vivo and bioinformatic experiments, we show that type III collagen (Col3) plays a tumor-restrictive role in human breast cancer. We demonstrate that Col3-deficient, human fibroblasts produce tumor-permissive collagen matrices that drive cell proliferation and suppress apoptosis in non-invasive and invasive breast cancer cell lines. In human triple-negative breast cancer biopsy samples, we demonstrate elevated deposition of Col3 relative to type I collagen (Col1) in non-invasive compared to invasive regions. Similarly, bioinformatics analysis of over 1000 breast cancer patient biopsies from The Cancer Genome Atlas BRCA cohort revealed that patients with higher Col3:Col1 bulk tumor expression had improved overall, disease-free, and progression-free survival relative to those with higher Col1:Col3 expression. Using an established 3D culture model, we show that Col3 increases spheroid formation and induces the formation of lumen-like structures that resemble non-neoplastic mammary acini. Finally, our in vivo study shows co-injection of murine breast cancer cells (4T1) with rhCol3-supplemented hydrogels limits tumor growth and decreases pulmonary metastatic burden compared to controls. Taken together, these data collectively support a tumor-suppressive role for Col3 in human breast cancer and suggest that strategies that increase Col3 may provide a safe and effective therapeutic modality to limit recurrence in breast cancer patients.© 2024. The Author(s).