Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer

Abstract

Loss of BRCA1 p220 function often results in basallike breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basallike MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

Targeted inhibition of Wnt signaling with a bacterial toxin fragment suppresses breast cancer tumor-initiating/chemo-resistant cells

“…Thus, exposure to cisplatin may have turned the TcdB FBD -insensitive tumor into a sensitive one. These findings are consistent with our recent report that cisplatin treatment could lead to luminal to basal/mesenchymal cell fate changes, in part due to interstrand DNA crosslinks(24). Indeed, treatment with cisplatin increased expression of basal/mesenchymal genes, as well as Fzd7 in MMTV-PyMT tumors, whereas these changes were reduced in the presence of TcdB FBD(Fig.…”

“…For instance, recent studies suggest that Wnt signaling enhances the DNA repair pathways in ovarian cancers (40), and it has been also proposed that therapyinduced senescence promotes cancer cell stemness via Wnt signaling (41). In our study, it is likely that cisplatin treatment leads to an epithelial cell fate change toward a mesenchymal state (24), which may represent a dedifferentiation process that involves Wnt signaling. Lastly, Wnt signaling has been shown to contribute to immune invasion as well as systemic inflammation in the tumor microenvironment that drives cancer metastasis (42)(43)(44)(45).…”

“…S3A-B). This approach somatically inactivates Brca1 and Trp53 in luminal mammary epithelial cells (MECs), which are believed to serve as the cellular origin of BRCA1associated BLBC (26)(27)(28), leading to development of mammary tumors that closely resemble the human BLBC subtype (24). Overall, these three models represent mammary tumor types that are not good candidates for hormone or anti-HER2 therapies but can be treated by standard chemotherapy.…”

Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity

“…Erosion and consequent "smoothening" of the epigenetic landscape may underlie most (if not all) aspects of aging [69][70][71][72][73][74][75]. A lasting relocation of chromatin modifiers in response to prolonged stress signaling (e.g., aging-related DNA damage) can introduce non-random changes into the epigenome barriers in a manner that allows cell states to aberrantly transit towards other differentiation valleys, consequently leading to a loss of cell fate commitment.…”

Antitumor immunity in dMMR colorectal cancers requires interferon-induced CCL5 and CXCL10

“…The data was processed using the Seurat package for R (v3.0) as described previously. 33 Briefly, cells with either a unique gene count over 2,500 or less than 200 as well as genes found in fewer than 3 cells were filtered out. Principle component analysis (PCA) was used to visualize and explore these datasets and we used the default settings of the RunTSNE function to summarize the PCA with tSNE dimensionality.…”