Mammary epithelium is hierarchically organized, with multipotent basal mammary stem cells (MaSCs) sit at the top of the hierarchy, giving rise to both luminal and basal mammary epithelial cells (MECs) during fetal development or upon transplantation to cleared mammary fat pad. Recent studies suggested that most breast cancers, including basal-like breast cancer, might originate from luminal cells, rather than from basal MaSCs, and that oncogenic events, such as ectopic expression of PIK3CA(H1047R) mutation, could induce multipotency in committed luminal cells, leading to acquisition of a MaSC-like phenotype by luminal MECs. TP53 is the most commonly mutated gene in human breast cancer; in particular, its inactivating mutations have been found in most basal-like and claudin-low breast cancer cases, raising a question as to whether TP53 loss-of-function mutations play a key role in dedifferentiation of committed luminal cells to multipotent MaSC-like cells. To study this, we induced disruption of Trp53 conditional knockout alleles in a small number of luminal MECs, either by transient Cre expression from intraductally injected Cre adenovirus under the control of the Keratin 8 (K8) promoter (Ad-K8-Cre virus) or by tamoxifen-induced transient activation of the CreER fusion driven by the same K8 promoter (K8-CreER mice). By in situ lineage-tracing, we found that induced loss of p53 in K8+ luminal cells led to their clonal expansion (by outcompeting their wild-type neighbors), due to increased cell cycle progression and impaired apoptosis control. However, p53-loss in luminal MECs did not directly affect their luminal identity, as determined by flow cytometry, immunostaining, and microarray expression profiling. Intriguingly, all induced female mice eventually developed mammary tumors. The majority of these tumors were large, fast growing claudin-low mammary tumors, based on histological and microarray analyses; a small number of these tumors exhibited features of basal-like mammary tumors. These data demonstrate that although p53 does not dictate the luminal MEC fate directly (i.e., loss of p53 does not directly lead to luminal-to-basal or mesenchymal transition), its inactivation facilitates loss of the luminal identity and predisposes luminal cells to development of claudin-low or basal-like breast tumors, thus in a way similar to the role of p53 in restricting reprogramming of somatic cells to induced pluripotent cells. Lastly, although it has been suggested that claudin-low breast cancer may originate from transformation of basal cells, our data support that upon p53-loss, claudin-low breast cancer can also have a luminal origin.

Citation Format: Luwei Tao, Ying Xie, Zhe Li. Inactivation of p53 in mammary luminal cells leads to their clonal expansion and facilitates development of mammary tumors with loss of luminal identity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3689.