A novel strategy to combat advanced prostate cancer utilized a replication incompetent retrovirus that contained the mouse mammary tumor virus (MMTV) promoter within the retroviral vector to allow transcription of antisense c-myc gene within target prostate tumor cells.
Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer.
Amplification of the proto-oncogene c-myc has been identified as one of the most common genetic alterations in prostate cancer, thus making it an attractive therapeutic target.
Finally, the expression levels of TRPS1, EIF3S3 and MYC were measured in freshly frozen clinical samples of benign prostate hyperplasia (BPH), as well as untreated and hormone-refractory prostate carcinoma.
By using a retroviral infection strategy followed by tissue recombination we have created a model of human prostate cancer that demonstrates that the c-MYC gene is sufficient to induce carcinogenesis.
These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function.
Although most amplified genomic regions tended to be large, amplifications at 8q24.21 were of particular interest because the affected regions are relatively small, are found in multiple cell lines, are located near MYC, an oncogene strongly implicated in prostate tumorigenesis, and are known to harbor SNPs that are associated with inherited susceptibility for prostate cancer.
Thus, it is critical to determine whether MYC protein is elevated in human prostate cancer, and if so, at what stage of the disease this elevation occurs.
Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1.
In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells.
MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.
Forty-nine tagging SNPs including three previously reported significant variants (rs1447295, rs6983267, rs16901979) and seven variants in the 5' upstream region of the MYC proto-oncogene were tested for association with susceptibility to PC and tumor aggressiveness in 596 histologically verified PC cases and 567 ethnically matched controls.