Folate receptor overexpression is associated with poor outcome in breast cancer

Abstract

The high affinity folate receptor is a membrane-associated glycoprotein that is preferentially expressed in cancers of epithelial origin and rarely expressed in normal cells. We examined its expression pattern in breast cancer, utilizing a tissue microarray containing samples from 63 invasive breast cancers from women with divergent clinical outcomes. Thirty-three women comprised the poor outcome group with a median time to recurrence of 1.9 years. Thirty women, the good outcome group, were free of recurrence for a minimum of 7 years after diagnosis. The intensity of folate receptor staining was strongly correlated with outcome. There were two summary categories of staining intensity: weak (n 5 42) or strong (n 5 21). In the strong staining group, 17 of 21 women (81%) have recurred and their median survival is 2.4 years. In the weak staining group, 16 of 42 women (38%) have recurred. Their median survival is not estimable. After adjustment for tumor size, nodal status, ER status, adjuvant therapy, histology and tumor grade, strong staining for the folate receptor remained significantly associated with poor outcome, p < 0.001. Our work requires validation in a larger cohort, but supports the possibility of using folate receptor-targeted approaches in the management of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: folate receptor; breast cancer; prognosis Folic acid and its reduced congeners are required for one carbon transfer reactions that are used in the biosynthesis of nucleotide bases, amino acids and other methylated compounds, and consequently, they are needed in larger quantities by proliferating cells. Physiological folates are transported into cells by either a low affinity reduced folate carrier (K m 5 10 25 M) or a high affinity folate receptor (K d 5 10 210 M). [1][2][3][4][5] The reduced folate carrier is ubiquitously expressed and constitutes the sole folate uptake pathway for most normal cells.The high affinity receptor is a glycosylphosphatidylinositolanchored membrane protein originally identified as a mAb-defined antigen in placenta and trophoblastic cells. It is rarely expressed or inaccessible in most normal cells. However, it is upregulated in select cancers of epithelial origin. 6 Distribution and binding studies of the high affinity folate receptor have shown high expression in the majority of ovarian cancers, and lesser degrees of positivity in kidney, breast, uterine and lung cancers. 6-10 Studies in ovarian cancer have shown an association between folate receptor overexpression and tumor aggressiveness. 7,[11][12][13] Studies of folate receptor expression in breast cancers have found varying results, depending on the techniques used and tissues analyzed. Ross et al. measured mRNA for the folate receptor and found levels to be elevated in five cancers when compared with normal breast specimens; however, the degree of elevation was 10-fold less than that seen in ovarian cancer. 10 Garin-Chesa et al. used a mouse monoclonal antibody LK26 to assess folate receptor expression in a variet...

Folate receptor alpha as a tumor target in epithelial ovarian cancer

“…only 20 high-stage, high-grade serous tumors lacked FRα expression in this study), very large sample sizes will be required to accrue sufficient numbers of patients with FRα-negative tumors for statistically meaningful comparisons. This makes analysis of the impact of FRα expression in ovarian cancer rather more difficult than in breast and uterine cancers; in these diseases, with strong FRα expression in a smaller proportion of patients, FRα expression is a negative prognostic factor [21,22].…”

Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

“…Such an observation is in line with our previous findings in primary colorectal cancers, as well as that observed in ovarian, breast and endometrial carcinoma. [9][10][11] In all of these tumor types including both primary and metastatic colorectal cancer, overexpression of FRa detected by immunohistochemistry had either a strong trend towards, or significantly correlated with a worse survival. Interestingly, however, a study that evaluated 119 non-small cell lung cancers found high FRa expression to be correlated with a better survival.…”

“…[5][6][7][8] Its expression in certain epithelial tumors such as ovarian, breast, endometrial and non-small cell lung carcinoma has been associated with tumor behavior. [9][10][11][12] Importantly, FRa expression is tumor specific, as it is significantly higher in tumor cells than in normal cells. 13 FRa also has a high affinity for folic acid; and the high affinity is maintained when folic acid is conjugated with other molecules.…”

Expression of folate receptors in nasopharyngeal and laryngeal carcinoma and folate receptor-mediated endocytosis by molecular targeted nanomedicine

“…The FR is rarely expressed in normal tissues, 1,2 is highly expressed in breast cancer, endometrial cancer, nonmucinous ovarian adenocarcinoma, lung cancer, kidney cancer, and pancreatic cancer, and is known as a tumor-associated antigen. [3][4][5][6] Folic acid (FA) is a water-soluble B vitamin, and is used in cells to synthesize thymine, which is critical for DNA synthesis, methylation, and repair. Folic acid is small (441 Da), stable over a broad range of temperatures and pH values, inexpensive, and nonimmunogenic.…”