妊娠相关乳腺癌中WNT和Notch的串扰

Introduction Pregnancy-Associated Breast Cancer (PABC) is defined as breast cancer diagnosed during pregnancy, lactation, or throughout the post-partum period. Approximately 1 in 3000 pregnant women will be diagnosed with this condition. The purpose of this study was to identify cell-of-origin and relevant signaling pathways implicated in the development and progression of PABC. Methods Immunohistochemistry was used for lineage tracing and protein expression patterns. Tumor-free survival calculations were made to asses tumor onset phenotypes in transgenic mice. Western blot was used to determine protein expression differences in comparative genotypes. Unpublished Data We have generated a PABC mouse model by crossing oncogenic Kras G12D with WAP-Cre mice. These mice develop tumors in a pregnancy-dependent manner that are histologically heterogeneous as well as estrogen and progesterone receptor negative. Our model recapitulates many features of PABC, including aggressive biological nature and frequent lung metastasis. Indeed, nearly all mice developed distant lung tumors during the lactational period. Preliminary studies using this model suggest that alveolar progenitor cell populations may represent the primary cell-of-origin in PABC. Lineage tracing in virgin mammary glands revealed very few cells labeled by WAP-Cre. Interestingly, mice that express Kras G12D exhibited drastic expansion of WAP-labeled cells, along with the development of precancerous lesions, even before pregnancy. WNT and Notch, two evolutionarily conserved pathways, regulate the fate of alveolar progenitors in normal mice, where dysregulation of these pathways facilitates oncogenic transformation and rapid tumor formation. Deletion of Notch3 significantly delayed Kras-driven tumor onset. Surprisingly, deletion of Jagged1, a Notch ligand, accelerated tumor onset. Further lineage tracing shows that deletion of Notch3 reduced the number of WAP-labeled progenitor population. Contrastingly, Jagged1 deletion leads to an expansion of WAP-labeled cells. Interestingly, despite accelerated tumor onset, deletion of Jagged1 significantly reduced the incidence of lung metastasis. In all mice, some percentage of tumor histology demonstrated a squamous phenotype. Deletion of Jagged1 resulted in 100% of these tumors developing a squamous phenotype. Overexpression of beta-catenin, the signaling effector of WNT, has been shown to promote squamous transdifferentiation. We show an increase in beta-catenin associated with the deletion of Jagged1. Additionally, strong positive immunostaining for non-phosphorylated, active, beta-catenin in Kras;WAP-Cre tumors was seen. Conclusions These findings suggest a crosstalk between Notch and WNT signaling. We propose that WAP-labeled alveolar progenitor cells serve as the cell-of-origin in PABC and that Notch and WNT signaling are key factors in tumor initiation, progression, and metastasis.