Basal-like breast cancers make up an aggressive subtype of breast cancer with diverse intratumor cell heterogeneity and poor clinical outcomes. These cancers are predominantly triple-negative cancers such that they lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Evidence suggests that basal-like cancers arise from luminal mammary epithelial cells that acquire basal-like traits during tumorigenesis, a process known as cell plasticity. These cancers also present with dramatic remodeling of stromal cell populations such as fibroblasts and immune cells, which become rewired to form a pro-tumorigenic niche. An improved understanding of the cellular mechanisms that drive epithelial plasticity and stromal remodeling may therefore help advance treatment avenues for basal-like breast cancer. This dissertation describes important roles for the Hippo signaling pathway, a pathway involved in development and stem cell traits, in basal-like breast cancer pathogenesis. Using genetic mouse models, we demonstrate that deletion of the Hippo pathway kinases large tumor suppressor kinase (LATS)1 and LATS2 (LATS1/2) in mammary luminal epithelial cells leads to luminal-basal plasticity and the development of basal-like carcinomas through activation of the transcriptional regulators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). These carcinomas are accompanied by remodeling of the mammary stroma, including an accumulation of cancer-associated fibroblasts and a distinct deposition of extracellular matrix. We further present analyses suggesting that LATS1/2 inactivation promotes a tumor-associated niche through reciprocal epithelial-stromal signaling. Together, these results implicate the Hippo pathway as a critical mediator of homeostasis in the mammary gland and suggest that Hippo dysregulation drives basal-like breast cancer initiation by promoting mammary epithelial transformation and stromal remodeling. / 2025-10-29T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/49437 |
| Date | 30 October 2024 |
| Creators | Kern, Joseph George |
| Contributors | Varelas, Xaralabos |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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