Gene expression profiles and the TP53 mutation status are powerful prognostic markers of breast cancer

Abstract

There is compelling evidence from transgenic mouse studies and analysis of mutations in human carcinomas indicating that the TGF-β signal transduction pathway is tumor suppressive. We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of mammary carcinomas. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the type II TGF-β receptor (TβRII). There is also evidence that TGF-β can enhance the progression of tumors. This hypothesis is being tested in genetically modified mice. To attain complete loss of TβRII, we have generated mice with loxP sites flanking exon 2 of Tgfbr2 and crossed them with mice expressing Cre recombinase under control of the MMTV promoter/enhancer to obtain Tgfbr2 mgKO mice. These mice show lobuloalveolar hyperplasia. Mice are being followed for mammary tumor development. Tgfbr2 mgKO mice that also express polyoma virus middle T antigen under control of the MMTV promoter (MMTV-PyVmT) develop mammary tumors with a significantly shorter latency than MMTV-PyVmT mice and show a marked increase in pulmonary metastases. Our data do not support the hypothesis that TGF-β signaling in mammary carcinoma cells is important for invasion and metastasis, at least in this model system. The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2 flox/flox mice were crossed to attain Tgfbr2 fspKO mice. The loss of TGF-β responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach with high penetrance by 6 weeks of age. Both epithelial lesions were associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. TGF-β signaling in fibroblasts thus modulates the growth and oncogenic potential of adjacent epithelia in selected tissues. More recently, we have examined the effects of Tgfbr2 fspKO fibroblasts on normal and transformed mammary epithelium. We analyzed the role of TGF-β signaling by stromal cells in mammary tumor progression. To avoid the possibility of endogenous wild-type fibroblasts masking potential effects of Tgfbr2 fspKO cells on tumor progression, we implanted PyVmT mammary carcinoma cells with Tgfbr2 fspKO or wildtype fibroblasts in the subrenal capsule of nude mice. Mamm...

Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors

“…Our data suggest that loss of p53 (by inactivation or mutation), one of the most common events occurring in cancer, might contribute to the upregulation of Cdc25B observed in many types of tumors. In agreement with this, Cdc25B was identified in a set of genes more highly expressed in primary breast tumors with p53 mutations (Troester et al, 2006;Langerod et al, 2007). As many p53 mutants not only act through dominant-negative function but also acquire a gain-of-function, notably by enhancing the activity of NF-Y (Di Agostino et al, 2006), the increased expression of Cdc25B in mutant p53 tumors (Troester et al, 2006;Langerod et al, 2007) may stem not only from loss of WT p53 repressive activity but also from the gain of functional properties of the mutant protein.…”

762 Prognostic and Predictive Value of TP53 Mutations in Node-positive Breast Cancer Patients Treated with Anthracycline-or Anthracycline/taxane Based Adjuvant Therapy – Results From the BIG 02-98 Phase III Trial

“…The presence of mutated p53 was associated with patient characteristics of increased age and postmenopausal status, and tumor characteristics of ductal morphology, higher grades and ER/PR negativity, in agreement with previous studies [5,34,35]. The highest rates of mutations were seen in the HER2 and triplenegative subtypes, as reported in other studies [12,36,37]. Most mutations were found at classical hotspot codons and were loss of function mutations as assessed in yeast functional assays [17].…”

“…A reported alternative for identification of 'functional' loss of wild-type p53 is a p53 transcriptional fingerprint. Several gene expression signatures have been reported that distinguish between wild-type and mutant p53 [36,43,44]. Interestingly some TP53 wild-type tumors expressing the mutation-associated 32-gene signature behaved aggressively, while some TP53 mutant tumors lacking the signature had favorable outcome [43].…”

Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information

“…Patients with molecularly defined luminal B tumors show highest mortality after 5-8 years. 22 Late relapse of the latter subtype may be triggered by discontinuation of endocrine therapy or may reflect its natural history and intrinsic aggressiveness. As such, there is a clear need to prospectively identify patients with luminal B cancers, particularly those in the lymph node-negative category, who may benefit from adjuvant chemotherapy.…”

“…39 TP53 alterations whether detected by molecular or immunohistochemical assays have been shown to be a marker of poor prognosis and to be predictive of treatment response by some but not all investigators. 7,12,15,22,38 Of note, when we substituted either PR or TP53 for Ki67 marked variation was seen in the distribution of the luminal subgroups with associated poor kappa statistics. These findings indicate that the three methods employed in this study identified different patients as being of poor prognosis, thereby limiting the clinical utility of the Ki67 classification alone.…”