Viral Sequences Found In Breast Cancer Samples

PARIS--A newly identified segment of an RNA retrovirus may be implicatedin as many as one third of breast tumors, James Holland, MD, of Mount SinaiMedical Center, NY, said at the Seventh International Congress on Anti-CancerTreatment (ICACT). The segment of the putative virus, thought to be a humanmammary tumor virus (HMTV), was discovered in the laboratory of Dr. BeatrizPogo at Mount Sinai.

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

"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 of52 breast cancers in men that have been examined to date.

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

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

Potential Clinical Impact

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

In addition, he noted, the HMTV sequence has been detected in up to75% of breast cancer patients whose mother also had breast cancer, in 82%of those whose mother and maternal grandmother had breast cancer, and in86% of those whose mother, maternal grandmother, and maternal aunt hadbreast 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 andsisters but also grandmothers and aunts," he urged.

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

Four Proposed Types Of Breast Cancer

Mode of Transmission

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

"This suggests a method of potential transmission that would notbe dissimilar from that of the mouse," Dr. Holland said. He notedthat the offspring of mice with the MMTV have a reduced incidence of breastcancer if they are nursed by foster mothers.

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