Abstract
Breast cancers that are “triple-negative” for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.
Highlights
The dire need for more effective treatments for aggressive breast cancers has motivated intensive investigations into their cellular and molecular etiology
Triple-negative breast cancers (TNBC) include the Claudin-low molecular subtype [3], which is characterized by greatly reduced expression of intercellular junction components and by activation of molecular pathways associated with epithelial-to-mesenchymal transition (EMT), cancer stem cells, and the immune response [4]
In the context of a brain carcinoma model initiated by T121, apoptosis appears to be the critical function of the normal p53 allele that is the target of selective pressure [21]
Summary
The dire need for more effective treatments for aggressive breast cancers has motivated intensive investigations into their cellular and molecular etiology. Breast cancers classified as ‘‘triplenegative’’ by clinical diagnostic markers (ESR1, PGR, and HER2 negative) are heterogeneous in their clinical behavior, morphology, and molecular biology. Triple-negative breast cancers (TNBC) typically express the Basal-like molecular signature, TNBC and Basal cancer classifications are frequently used interchangeably. They are not completely synonymous [1,2]. Most triple-negative breast cancers are invasive ductal carcinomas, but TNBCs include the metaplastic, medullary, and adenocystic histologic special types, distinctive morphologies that are prevalent among Claudin-low tumors [4]. Mouse models that mimic the complexity of TNBC will be invaluable tools for defining the diverse cellular biology and behavior of these tumors and for rigorously triaging new drug candidates
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