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Title: Cooperativity of Rb, Brca1, and p53 in Malignant Breast Cancer Evolution}
Article:
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.
Introduction:
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 “triple-negative” 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, thus TNBC and Basal cancer classifications are frequently used interchangeably. However, they are not completely synonymous[1],[2]. TNBCs also 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]. Histologically, most triple-negative breast cancers are invasive ductal carcinomas, but TNBCs also include the metaplastic, medullary, and adenocystic histologic special types, distinctive morphologies that are prevalent among Claudin-low tumors[4]. TNBCs are insensitive to endocrine therapy and HER2 antagonists, but they are sensitive to chemotherapy. Nevertheless, long-term patient outcomes are poor due to high rates of relapse and acquired chemoresistance[5],[6]. 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. Basal-like breast cancers often simultaneously inactivate three tumor suppressors that are infamous for their roles in familial cancers: Rb( RB1)[7], p53( TP53)[8], and BRCA1[9]. p53 is mutated in 20–30% of human breast cancers and defective pathway intermediates also increase breast cancer risk[10]. Moreover, nearly all Basal-like cancers with BRCA1 mutation have concomitant p53 mutation[11]. Germline BRCA1 mutation predisposes early-onset breast cancers that are often triple-negative and that correlate with Basal-like tumors in microarray analyses[9]. BRCA1 mutation accounts for nearly half of familial breast cancers( OMIM 604370), but BRCA1 is also down-regulated in sporadic breast tumors without germline mutation[12]. The overall effect of BRCA1 loss is likely pleiotropic. The best studied function of BRCA1 is in orchestrating DNA double-strand break repair through homologous recombination or non-homologous end-joining. The importance of defective DNA repair in breast cancer is underscored by the observation that all known genes associated with inherited forms of the disease safeguard genomic integrity[13]. BRCA1 also functions as a transcription factor[14] that appears to be required for the differentiation of stem/progenitor cells into mature luminal cells[15]. This finding is consistent with the recent characterization of BRCA1-associated tumors as aberrant luminal progenitor cells[16]. The pair-wise cooperativity of Brca1 and p53 in mammary tumorigenesis has been studied in mouse models[17]. We and others have investigated the impact of combined Rb and p53 inactivation on mammary tumorigenesis in vivo[18]–[20]. We showed that following Rb perturbation in vivo, tumor progression is limited largely by p53-dependent apoptosis, and that loss of the second p53 allele in MFT121+/p53f/+ tumors is likely a prerequisite for mammary tumor progression[19], since the vast majority of tumors lose the wild type p53 allele during tumorigenesis. 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]. Our motivation to combine Rb inactivation with Brca1 and p53 mutation derives, in part, from the observation that the Rb gene is among the most frequently deleted loci in Brca1/p53-mutated mouse tumors[22], indicating that Rb is a critical barrier to tumor progression. Rb pathway inactivation is strongly associated with human triple negative breast cancers. A cardinal feature of basal-like breast cancers is the abundant expression of the “proliferation cluster” genes[7], which include many E2F-regulated genes that are de-repressed following Rb inactivation. In human breast cancers, reduced pRb activity correlates with higher tumor grade[23], but also predicts improved chemotherapy responsiveness[24]. The Rb gene itself is mutated in breast cancer[25], and recent genomic studies have indicated an overrepresentation of mutations within pRb-binding sites of human gene regulatory domains[26]. In this study we show that mammary tumors caused by inactivation of the pRb family( pRbf) of proteins( pRb, p107, p130), together with Brca1 and p53 inactivation, mimic several aspects of the most aggressive forms of breast cancer, including rapid tumor progression, poor differentiation, distant metastasis, necrosis, metaplasia, and genomic instability. Our findings illustrate the compounding effect of acquiring multiple tumor suppressor mutations during tumor evolution and underscore the distinct requirements of each of these canonical tumor suppressor proteins.
Discussion:
Here we report a highly penetrant engineered mouse model of TNBC. Our previous work showed that when pRbf and p53 are simultaneously perturbed in mammary epithelium, adenocarcinomas develop with long latency, suggesting a requirement for additional oncogenic events. However, these mouse tumors displayed only limited chromosomal copy number aberrations[19]. Because genomic instability is a hallmark of malignant transformation[35], especially among BRCA1 familial cancers[36] and aggressive sporadic breast cancers[37], we hypothesized that Brca1 mutation would accelerate the tumor development we observed following dual inactivation of pRbf and p53. Our results show that concomitant inactivation of all three tumor suppressor pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, malignant carcinomas. Although Brca1 inactivation accelerated tumorigenesis compared to TP tumors, we observed no statistical difference between chromosomal copy number transitions in tumors with or without Brca1, despite the extensive CNAs observed by others in Brca1/p53 tumors[22]. The pRb-regulated cell cycle network is frequently disrupted in TNBC tumors[7],[26],[37],[38], and the Rb locus is among the most frequently lost in Brca1/p53 mouse tumors[22], indicating that there is strong selective pressure for Rb pathway inactivation. We speculate that direct inactivation of pRbf by T121 may allow TBP cells to escape this rate-limiting barrier of transformation without accruing numerous chromosomal aberrations. Thus, in the context of defective pRb and p53 function, tumor progression may be unrelated to the proportion of the genome altered by copy number alterations. It will be important to determine the effect of Brca1 loss on the abundance and identities of somatic mutations that are not detectable by CGH. The importance of p53 mutation in breast cancers is well documented and is confirmed in the present study. The dual inactivation of pRbf and Brca1 caused markedly increased cell death that was reduced by p53 mutation. p53-independent cell death likely remains a significant barrier to tumor progression among TBP tumors and may account, in part, for the observed loss of genomic regions that harbor cell death regulatory genes, most notably on chr4 where the p53 paralog p73 resides. Identifying the genomic alterations that are conserved across species will be useful in evaluating the impact of the myriad of CNAs observed in breast cancers and may help to explain the heterogeneity of TNBCs. Brca1 mutation not only accelerated tumor development but also shifted the tumor spectrum. Whereas T121/p53 mouse tumors often resembled the Luminal-B molecular subtype breast cancers, which show relatively abundant expression of luminal epithelial cell differentiation markers, TBP tumors consistently shared features of Basal-like and Claudin-low molecular subtypes. Others have argued that Basal-like and Claudin-low gene expression signatures reflect progenitor and stem cell phenotypes, respectively[4],[16], consistent with a role for Brca1 in mediating stem/progenitor cell maturation[15]. Loss of BRCA1 activity may also alter tumor phenotype through deregulation of the EMT inducer SLUG[39]. The CGH analysis of our mouse tumors revealed CNAs consistent with mutations observed in genomic surveys of human breast cancers[40],[41]. Similar to the studies of human tumors, we saw increased copy numbers of known oncogenic driver genes, including myc, egfr, crebbp, jak1, H-ras, and K-ras, as well as enrichment of pathways implicated in tumor progression, including the WNT signaling pathway, regulation of actin cytoskeleton, focal adhesion, cell shape, and mobility proteins. Far fewer investigations have focused on genetic deletions and cancer development mechanisms. We also found decreased copy numbers of known tumor suppressors, including map2k, ppp2r, and pten. Given the strong similarities between our mouse model and aggressive human breast cancers, the TBP model provides an invaluable preclinical platform to identify and assess potential therapeutics for aggressive and chemoresistant breast cancer subtypes[42],[43].
These studies establish a unique animal model of aggressive forms of breast cancer for which there are no effective , targeted treatments . Rb , p53 , and Brca1 are associated with inherited forms of cancer , but defects in these pathways are also found together in a subset of breast cancer patients without a family history of the disease . Simultaneous inactivation of all three pathways causes more aggressive disease than do pair-wise combinations , indicating that the pathways play non-overlapping roles in tumor prevention .