Transcription Factor YB-1 Predicts Resistance Chemoresistance and Natural Prognosis

SAN ANTONIO—The 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 23^rd 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 overexpression."

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 patient groups.

In the group without postoperative chemotherapy—who offer insight into YB-1’s effect on natural disease course—30% 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 regimens.

"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 PAI1.

"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."