Progression of Hormone-Dependent Mammary Tumors After Dormancy: Role of Wnt Pathway

Abstract

The cancer stem cell theory suggests the existence of cells within breast cancers that possess the ability to self-renew and differentiate, albeit in a deregulated manner, which sustains tumor progression. Therefore, latent breast tumors and/or their metastasis may eventually resume growth thorough signals impacting on cancer stem cells and their niche. Since it has been determined that the Wingless Related Protein (Wnt) signaling is a likely niche factor and regulator of Mammary Stem Cells dynamics, it is conceivable that this pathway play a significant role in the “awakening” of dormant tumors. We have previously shown that in virgin females, MMTV-induced pregnancy-dependent (ER+PR+) tumor transplants were able to remain dormant for up to 300 days, but were able to resume growth after hormone stimulation. In a subsequent transplant generation, all these tumors became ER−PR− and grew in virgin females, indicating that cancer dormancy facilitated progression to hormone-independence. Our data also showed that mutations altering expression of genes involved in the Wnt pathway were prone to be selected during progression. To gain more insight into the mechanisms underlying these observations, we compared the gene expression profile of tumors that either underwent or not dormancy before progressing to hormone-independency. Confirming our previously reported data, we found that the most significant up-regulated gene in hormone-independent tumors that progressed after dormancy was Wnt1. In addition, in this group we have determined a systematic down-modulation of previously described mediators of normal pubertal mammary gland development. Using a hierarchical clustering analysis to classify breast cancer patients, we have also identified a specific group of breast carcinomas with significant modulation of genes also deregulated in the MMTV-induced tumors that resumed growth after dormancy. Interestingly, that group of human samples was mainly composed by patients with basal-like breast carcinomas, which also showed down-regulation of genes associated to pubertal mammary development. Therefore, we believe that the cluster of co-regulated genes in basal human breast cancer and mouse mammary tumors resuming growth after dormancy might be mechanistically associated to the activation of Wnt pathway, which might induce proliferation from mammary progenitor basal cells.