Effects of the Breast Tissue Microenvironment on the Progression of Breast Cancer

Breast cancer is the second most common cancer in women. The breast tumor will remodel its surrounding environment to make it more permissive to invasion and eventual metastasis through alterations of the extracellular matrix (ECM), cells, and secretions. Examining these changes proves important as they give possible targets for therapeutics. There are multiple different risk factors for breast cancer and they all can cause changes in the normal breast environment. These changes in the normal breast microenvironment are critical to investigate as they can allow for the progression of breast cancer.
In this dissertation, first we examined the normal breast structure of mice groups with different generations of obesity. These matrices showed differences in the collagen structure, namely collagen curvature, that breast cells responded with increased migration and invasion when seeded on the ECM from mice with a high-fat dam. We then investigated if an increase in leptin concentration caused alterations in collagen curvature. Next, we investigated 3D tumor models and created a 3D bioprinted human obesity breast tumor model. After being characterized, both 2D breast cancer cell culture and our 3D tumor spheroid model were treated with different extracellular vesicle (EV) groups where we saw an increase in cell migration and invasion for those constructs treated with EVs from fibroblasts closer to the tumor. Finally, we examined the impact of chemotherapeutics on normal breast fibroblast ECM production. Those fibroblasts treated with doxorubicin had increased reactive oxygen species production and the ECM they generated had a curvier collagen structure, which caused breast cancer cells to have increased migration and invasion when seeded onto the generated ECM. Overall, through these studies we were able to show how different changes in collagen structure or proximity to a tumor can affect the progression of breast cancer cells to be more motile and invasive.

乳腺癌是女性中第二高发的癌症。乳腺肿瘤可通过改变细胞外基质（extracellular matrix, ECM）、细胞及分泌组分，重塑其周围微环境，使其更利于肿瘤侵袭与最终转移。探究此类变化具有重要意义，因其可为治疗策略提供潜在靶点。乳腺癌存在多种风险因素，均可引发正常乳腺微环境的改变。对这些正常乳腺微环境的变化开展研究至关重要，因为它们会推动乳腺癌的进展。
在本研究中，我们首先对不同代次肥胖小鼠的正常乳腺结构进行了检测。这些基质在胶原蛋白结构上存在差异，具体表现为胶原蛋白曲率的不同；当将乳腺细胞接种于高脂母鼠来源的ECM上时，乳腺细胞的迁移与侵袭能力显著增强。随后我们探究了瘦素浓度升高是否会引发胶原蛋白曲率的改变。接下来，我们开展了三维肿瘤模型的相关研究，并构建了生物打印的人类肥胖型乳腺肿瘤模型。在完成表征鉴定后，我们分别用不同的细胞外囊泡（extracellular vesicle, EV）组处理二维乳腺癌细胞培养体系与三维肿瘤球体模型；结果显示，经肿瘤邻近成纤维细胞来源的EV处理的构建体，其细胞迁移与侵袭能力均有所提升。最后，我们考察了化疗药物对正常乳腺成纤维细胞ECM生成的影响。经阿霉素（doxorubicin）处理的成纤维细胞，其活性氧生成量增加，且其所生成的ECM拥有更弯曲的胶原蛋白结构；这使得接种于该ECM上的乳腺癌细胞迁移与侵袭能力增强。综上，通过本系列研究，我们阐明了胶原蛋白结构的不同变化，以及与肿瘤的邻近程度，是如何促使乳腺癌细胞获得更强的迁移与侵袭能力的。