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
"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
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
"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
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.