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Viral Sequences Found In Breast Cancer Samples

Viral Sequences Found In Breast Cancer Samples

PARIS--A newly identified segment of an RNA retrovirus may be implicated in as many as one third of breast tumors, James Holland, MD, of Mount Sinai Medical Center, NY, said at the Seventh International Congress on Anti-Cancer Treatment (ICACT). The segment of the putative virus, thought to be a human mammary tumor virus (HMTV), was discovered in the laboratory of Dr. Beatriz Pogo at Mount Sinai.

In 37% of human breast cancer DNA specimens, the Mount Sinai researchers found a 660-base pair sequence that was more than 95% homologous to a region of the envelope gene of the mouse mammary tumor virus (MMTV) but had only minimal overlap with human endogenous retrovirus (HERV) sequences or any other known human genes. In contrast, the sequences were discernible in only 7% of breast fibroadenoma specimens and in about 3% of normal breast specimens.

"Viral isolates from different human breast cancers are not identical, which is exactly what virologists would expect," Dr. Holland noted. Interestingly, he said, HMTV sequences have not been detected in any of 52 breast cancers in men that have been examined to date.

To rule out the possibility that these findings might reflect contamination arising from the exquisite sensitivity of the polymerase chain reaction (PCR) method, the investigators used the Southern blotting technique to prove that the HMTV sequences are present in the DNA in its native state. By synthesizing peptides based on the sequences and raising antibodies against these peptides, the Mount Sinai group has been able to show that the sequences are not only translated to RNA but also expressed as protein in Western blots.

Although their attempts to clone the HMTV have not yet proven successful, they are doing a viral "walk" and gradually lengthening the sequences that can be ascribed to the virus. A region comprising the long terminal repeat (LTR) gene has been amplified and sequenced from breast cancer tissue and shown to be likewise homologous to the MMTV, with low homology to the endogenous retrovirus.

Potential Clinical Impact

The potential clinical impact of the virus is already becoming evident in studies of breast cancer kindreds, Dr. Holland said. He described a family in which five women--proband, two sisters, mother, and aunt--developed nine breast cancers, every single one of which manifested the HMTV sequence.

In addition, he noted, the HMTV sequence has been detected in up to 75% of breast cancer patients whose mother also had breast cancer, in 82% of those whose mother and maternal grandmother had breast cancer, and in 86% of those whose mother, maternal grandmother, and maternal aunt had breast cancer.

"I think that we should revise our concept of high-risk individuals, which is based on first-degree relatives, to include not only mother and sisters but also grandmothers and aunts," he urged.

Based on these results, Dr. Holland proposes that there are four different kinds of breast cancer, making breast cancer a heterogeneous disease .

Four Proposed Types Of Breast Cancer

  1. Breast cancers due to the BRCA1 gene, which is estimated to account for about 4% of cases.
  2. Breast cancers due to BRCA2, a less common genetic abnormality.
  3. Breast cancers associated with viral sequences homologous to the MMTV, which accounts for about 38% of cases.
  4. Breast cancers of unknown etiology, which may have various causes.
    Based on a presentation by Dr. James Holland, Mount Sinai Medical Center, New York.

Mode of Transmission

The researchers are also exploring the mode of transmission of the viral sequences and their possible role in the pathology, pathogenesis, and treatment of breast cancer. In samples from a pregnant woman with breast cancer, the viral sequences were found in breast milk and in the lymphocytes of the arterial and venous placental blood.

"This suggests a method of potential transmission that would not be dissimilar from that of the mouse," Dr. Holland said. He noted that the offspring of mice with the MMTV have a reduced incidence of breast cancer if they are nursed by foster mothers.

Dr. Holland predicts that HMTV will be of major significance regardless of whether it ultimately proves to be an exogenous causal agent or represents recombinations of endogenous viral sequences unique to breast cancer tissue.

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