SAN ANTONIOThe Y-box-binding protein-1 (YB-1)
appears to be a clinically significant tumor marker in breast cancer, according
to results of a pilot study presented by Nadia Harbeck, MD, PhD, at the 23rd
Annual San Antonio Breast Cancer Symposium.
Overexpression of this DNA-binding protein is associated with
drug resistance, especially to anthracycline-containing regimens, and with a
worse prognosis among patients who have not received postoperative
chemotherapy, said Dr. Harbeck, associate professor of obstetrics and
gynecology, Technical University of Munich.
YB-1 belongs to a class of highly conserved proteins that are
involved in transcription and transformation, she said. YB-1 binds to the
Y-box, an inverted CCAAT box, in the promoter region of the human multidrug
resistance 1 (MDR1) gene, which encodes P-glycoprotein.
A 1997 study (Nature Med 3:447-450, 1997) showed that nuclear
overexpression of YB-1 in a formerly drug-sensitive breast cancer cell line
induced MDR1 expression and multidrug resistance. The current pilot study was
designed to determine whether these in vitro data have any clinical
significance in breast cancer.
The study population was a group of 83 breast cancer patients
with a median follow-up of 5 years. For analysis, the patients were divided
into two subsets: those who had received postoperative chemotherapy (41
patients) and those who had not (42 patients). Most of the chemotherapy-treated
women had received anthracycline-containing regimens.
The patients’ tumor samples were tested for YB-1 expression
and for overexpression of HER-2-neu (also known as erbB2), urokinase
plasminogen activator (uPA), and plasminogen activator inhibitor 1 (PAI1).
These other tumor markers were examined to ensure that YB-1 was "adding
something new to the picture," Dr. Harbeck said, and not simply
duplicating information already provided by other well-established predictive
or prognostic factors.
In addition, the researchers looked for YB-1 expression in 12
benign breast tissue samples removed from women undergoing plastic surgery.
"There is no YB-1 expression whatsoever in normal breast
tissue," Dr. Harbeck reported. "But when we look at carcinoma tissue,
we see cytoplasmic YB-1 expression in the tumor cells as well as in the benign
tissue cells surrounding the tumor.
About two thirds of the patients’ tumors showed high
cytoplasmic expression of YB-1. Nuclear YB-1 expression was found in 11 of the
83 tumors, but in none of the benign cells surrounding them, she said.
Nuclear expression was well-correlated with cytoplasmic
expression. "In 10 of the 11 cases, if there was nuclear expression, there
was also high cytoplasmic expression in the tumor and/or the surrounding benign
breast tissue," Dr. Harbeck said. "Nuclear YB-1 expression was not
correlated with high uPA or PAI1 in the tumor tissue or with HER-2-neu
Because of the relatively small number of tumors with nuclear
YB-1 expression, the researchers concentrated on cytoplasmic YB-1 expression in
their clinical outcome correlations. YB-1 expression was predictive in both
In the group without postoperative chemotherapywho offer
insight into YB-1’s effect on natural disease course30% of the patients
with high YB-1 expression have relapsed, compared with none of the patients
without YB-1 overexpression.
Similar results were found in the chemotherapy-treated
patients: a 66% relapse rate among those with high YB-1 expression and no
relapses among patients whose tumors did not overexpress the protein.
"Patients with low YB-1 did well after postoperative
chemotherapy," Dr. Harbeck said. "But patients with high YB-1,
especially those with high YB-1 in the tumor and in the benign cells
surrounding the tumor, did significantly worse."
Most of the relapses occurred within the first 2 years, which,
he said, suggests that these patients did not benefit from the anthracycline-containing
"Our data suggest that high YB-1 expression is clinically
relevant and does correlate with tumor aggressiveness and resistance to
postoperative chemotherapy," Dr. Harbeck said.
In risk group stratification, she added, high YB-1 differs
significantly from other tumor biologic markers, such as HER-2-neu, uPA, and
"Although we cannot draw definite conclusions from this
pilot study," she said, "it does nicely confirm the in vitro data and
suggests that YB-1 is a potential target for tumor therapy."