Role of an Ethnically Disparate p53 Polymorphism at Codon 72 in Susceptibility to Mammary Tumorigenesis in a Humanized Mouse Model

Presentation Number: OR21-6
Date of Presentation: April 2nd, 2017

Ramesh T Gunaratna*1, Andres Santos1, Chandandeep Nagi2, Claudio Conti3 and Robin S L Fuchs-Young4
1Texas A&M Health Science Center, College Station, TX, 2Baylor College of Medicine, Houston, TX, 3Universidad Carlos III de Madrid, Madrid, Spain, 4Texas A&M University Health Science Center, College Station, TX


Outcome disparities in female breast cancer (BrCa) remain a persistent problem in the US, where AA patients tend to suffer reduced tumor free interval and survival compared to their European counterparts. This is due, at least in part, to the fact that AA women are more likely to develop early onset, aggressive and treatment refractory subtypes of BrCa. We investigated the possible contributions of an ethnically disparate polymorphism on the 72nd codon of p53, which encodes for either a proline (P) variant, which is more abundant in women of European descent (>70%), or an arginine (R) variant, which is more prevalent among African descendants (>60%). In vitro and in vivo studies have shown that these variants have differential ability to regulate cell cycle arrest, senescence and apoptosis, but the precise mechanisms in the mammary gland remain unresolved. We first investigated the effect of the variants on susceptibility to DMBA-induced mammary tumorigenesis in the humanized, homozygous, p53P and p53R mice. Mammary tumor latency was significantly shorter in p53R compared to p53mice, 21 vs. 71 days post-dosing, respectively (log-rank test, p=0.049, n=40). Tumor incidence was also higher in the p53R compared to p53P mice, 34.5% vs. 17.6%, respectively. To compare effects on oncogene-induced mammary tumorigenesis, p53 variant mice were bred with MMTV-Erbb2/neu genetic model (E-p53). While 100% of the animals developed mammary tumors, the effect on latency was similar to the DMBA model, with E-p53R mice displaying significantly reduced tumor latency compared to E-p53P, 122 vs. 173 days, respectively (p=0.01, n=53). The tumor growth rate in E-p53R mice was also significantly increased (35.85±4.5 vs. 22.66±3.8 mm3 per day). To elucidate the underlying molecular mechanisms, we explored expression of genes involved in tumor suppression. Paradoxically, significant upregulation of cell cycle arrest genes, p21, p16INK4a, and increased expression of senescence-associated Pai1, were seen in tissues from p53R mice. In addition, susceptible E-p53R glands had reduced levels of phospho-RB and increased Sudan Black B staining, demonstrating that an elevated number of cells were undergoing cell cycle arrest and senescence. Further analysis revealed that the E-p53R glands also had significantly elevated expression of Tnfα, Il6, Ccl4 and Relb, indicating an inflammatory response. These results are consistent with the association of the p53R variant with a proinflammatory senescence-associated secretory phenotype (SASP), which has been shown to enhance tumorigenesis and resistance to treatment in several tissues, including mammary gland. Together, these data indicate that the p53R variant stimulates mammary tumorigenesis through an increased SASP-driven inflammatory response, potentially contributing to the early onset, treatment refractory BrCa seen in the women of African descent.


Nothing to Disclose: RTG, AS, CN, CC, RSLF