The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

https://science.sciencemag.org/content/sci/235/4785/177.full.pdf

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

A retrovirus belonging to the family of recently discovered human T-cell leukemia viruses (HTLV), but clearly distinct from each previous isolate, has been isolated from a Caucasian patient with signs and symptoms that often precede the acquired immune deficiency syndrome (AIDS). This virus is a typical type-C RNA tumor virus, buds from the cell membrane, prefers magnesium for reverse transcriptase activity, and has an internal antigen (p25) similar to HTLV p24. Antibodies from serum of this patient react with proteins from viruses of the HTLV-I subgroup, but type-specific antisera to HTLV-I do not precipitate proteins of the new isolate. The virus from this patient has been transmitted into cord blood lymphocytes, and the virus produced by these cells is similar to the original isolate. From these studies it is concluded that this virus as well as the previous HTLV isolates belong to a general family of T-lymphotropic retroviruses that are horizontally transmitted in humans and may be involved in several pathological syndromes, including AIDS.

http://science.sciencemag.org/content/sci/220/4599/868.full.pdf

Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS).

Transcription of the c-fos proto-oncogene is greatly increased within minutes of administering purified growth factors to quiescent 3T3 cells. This stimulation is the most rapid transcriptional response to peptide growth factors yet described, and implies a role for c-fos in cell-cycle control. Transformation by c-fos may result from a temporal deregulation of this control.

Stimulation of 3T3 cells induces transcription of the c- fos proto-oncogene

Transfection of embryo fibroblasts by a human ras oncogene does not convert them into tumour cells unless the fibroblasts are established and immortalized before transfection. The embryo fibroblasts become tumorigenic if a second oncogene such as a viral or cellular myc gene or the gene for the polyoma large-T antigen is introduced together with the ras gene.

Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes.

Cell-Specific Regulation of the c-myc Gene by Lymphocyte Mitogens and Platelet-Derived Growth Factor

Analyses of DNA and RNA from avian leukosis virus (ALV)-induced lymphomas have provided strong evidence that, in most tumours, ALV induces neoplastic disease by activating the c-myc gene, the cellular counterpart of the transforming gene of MC29 virus. The data indicate that, as a rare event, the ALV provirus integrates adjacent to the c-myc gene and that transcription, initiating from a viral promoter, causes enhanced expression of c-myc, leading to neoplastic transformation.

Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis

Avian leukosis virus-induced tumors have common proviral integration sites and synthesize discrete new RNAs: oncogenesis by promoter insertion

We have used in situ chromosome hybridization techniques to map the human cellular counterparts (c-onc genes) of the transforming genes of two RNA tumor viruses on human meiotic pachytene and somatic metaphase chromosomes. We find that the human c-mos gene is located on chromosome 8 at a position corresponding to band 8q22 on the somatic map. The human c-myc gene is found on chromosome 8 at position 8q24. These regions on the long arm of chromosome 8 have been previously reported to be involved in specific translocations found in the M-2 subset of acute nonlymphoblastic leukemias. Burkitt lymphoma, and other forms of non-Hodgkin lymphoma, and a familial abnormality that predisposes to renal cell carcinoma. These results suggest that translocations of the human c-mos or c-myc genes may be causally related to neoplastic transformation.

https://www.pnas.org/content/pnas/79/24/7842.full.pdf

Two human c-onc genes are located on the long arm of chromosome 8

Viral complementary DNA (cDNA) sequences corresponding to the gag, pol, env, src, and c regions of the Rous sarcoma virus genome were selected by hybridizing viral cDNA to RNA from viruses that lack the env or src gene or to polyadenylic acid [poly(A)]-containing RNA fragments of different lengths and isolating either hybridized or unhybridized DNA. The specificities, genetic complexities, and map locations of the selected cDNA's were shown to be in good agreement with the size and map locations of the corresponding viral genes. Analyses of virus-specific RNA, using the specific cDNA's as molecular probes, demonstrated that oncovirus-infected cells contained genome-length (30-40S) RNA plus either one or two species of subgenome-length viral RNA. The size and genetic content of these RNAs varied, depending on the genetic makeup of the infecting virus, but in each case the smaller RNAs contained only sequences located near the 3' end of the viral genome. Three RNA species were detected in Schmidt-Ruppin Rous sarcoma virus-infected cells: 39S (genome-length) RNA; 28S RNA, with an apparent sequence of env-src-c-poly(A); and 21S RNA, with an apparent sequence of src-c-poly(A). Cells infected with the Bryan high-titer strain of Rous sarcoma virus, which lacks the env gene, contained genome-length (35S) RNA and 21S src-specific RNA, but not the 28S RNA species. Leukosis virus-infected cells contained two detectable RNA species: 35S (genome-length) RNA and 21S RNA, with apparent sequence env-c-poly(A). Since gag and pol sequences were detected only in genome-length RNAs, it seems likely that the full-length transcripts function as mRNA for these two genes. The 28S and 21S RNAs could be the active messengers for the env and src genes. Analyses of sequence homologies among nucleic acids of different avian oncoviruses demonstrated substantial similarities within most of the genetic regions of these viruses. However, the "common" region of Rous-associated virus-0, an endogenous virus, was found to differ significantly from that of the other viruses tested.

Size and genetic content of viral RNAs in avian oncovirus-infected cells.

We have shown that the human cellular oncogene c-myc is composed of three exons and is transcribed from two initiation sites separated by 175-base-pair DNA in HeLa cells. For both resulting mRNA species, exon 1 composes the 5' untranslated region and the initiator methionine is located 16 base pairs down-stream from the 5' splice acceptor of exon 2. In a non-Hodgkin lymphoma, Manca, harboring a t(8; 14) translocation, c-myc gene is broken within intron 1, and its exons 2 and 3 are translocated to a site between the heavy chain joining region cluster and C mu-coding DNA segment of the immunoglobulin heavy chain locus. The translocated c-myc gene is transcribed from points within intron 1 but is apparently still translated from the same methionine codon as the mRNA from the unrearranged c-myc gene. The nucleotide sequence of the c-myc gene shows that a region of exon 1 is highly complementary to a region of exon 2. Thus the mRNA from the untranslocated c-myc gene, as opposed to that of the translocated c-myc gene, could form a stable stem-loop structure (delta Go = -90 kcal/mol; 1 cal = 4.184 J) where the initiator AUG would be located within the loop. In view of the bind-and-scan model for the initiation of eukaryotic translation, we propose that such a secondary structure will severely hinder the translation. We further propose that the c-myc gene is often activated by translocation through the escape from such a translational suppression.

William S. Hayward

Papers

Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis

Avian leukosis virus-induced tumors have common proviral integration sites and synthesize discrete new RNAs: oncogenesis by promoter insertion

Two human c-onc genes are located on the long arm of chromosome 8

Size and genetic content of viral RNAs in avian oncovirus-infected cells.

Activation of the c-myc gene by translocation: a model for translational control