B7-H4 Is Highly Expressed in Ductal and Lobular Breast Cancer

Abstract

Purpose: This study was designed to investigate the expression of B7-H4 protein, a member of the B7 family that is involved in the regulation of antigen-specific immune responses, in normal breast and in primary and metastatic breast carcinomas.Experimental Design: Archival formalin-fixed tissue blocks from breast cancers and normal somatic tissues were evaluated for B7-H4 expression by immunohistochemistry with manual and automated image analysis. The proportion of B7-H4-positive cells and the intensity of B7-H4 staining were compared with histologic type, grade, stage, hormone receptor status, and HER-2/neu status.Results: B7-H4 was detected in 165 of 173 (95.4%) primary breast cancers and in 240 of 246 (97.6%) metastatic breast cancers. B7-H4 staining intensity was greater in invasive ductal carcinomas [24.61 relative units (RU)] and in invasive lobular carcinomas (15.23 RU) than in normal breast epithelium (4.30 RU, P = 0.0003). Increased staining intensity was associated with negative progesterone receptor status (P = 0.014) and history of neoadjuvant chemotherapy (P = 0.004), and the proportion of B7-H4-positive cells was associated with negative progesterone receptor (P = 0.001) and negative HER-2/neu (P = 0.024) status. However, there was no statistically significant relationship between the proportion of B7-H4-positive cells or staining intensity and grade, stage, or other clinicopathologic variables. Low levels of B7-H4 expression were also detected in epithelial cells of the female genital tract, lung, pancreas, and kidney, but B7-H4 was generally absent in most other normal somatic tissues.Conclusions: The nearly ubiquitous expression of B7-H4 in breast cancer, independent of tumor grade or stage, suggests a critical role for this protein in breast cancer biology.

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

“…Our current study demonstrates that clear cell RCC tumors of the kidney express B7-H4. Sporadic expression of B7-H4 was also noted in some distal convoluted tubules of the kidney, as previously reported (5). In contrast, proximal tubules of the kidney, from which clear cell RCC tumors originate, were devoid of B7-H4 staining (22)(23)(24).…”

“…Recent reports, however, indicate focal and infrequent protein expression in certain somatic tissues, including distal convoluted tubules of the kidney, ductal and acinar cells of the pancreas, endometrial glands, transitional epithelia of the ureter and bladder, bronchial epithelium of the lung, and columnar epithelium of the gallbladder (5). Additionally, B7-H4 has been found to be aberrantly expressed at high levels in human serous, endometrioid, and clear cell ovarian carcinoma; ductal and lobular breast cancer; and lung cancer (5,6,21). This overexpression of B7-H4 by malignant tissues may render B7-H4 a particularly useful target for facilitating antitumoral immunotherapeutic responses.…”

“…Robust B7-H4 protein expression is primarily restricted to activated T cells, B cells, monocytes, and dendritic cells. Weak or sporadic expression of B7-H4 has also been observed in some peripheral tissues, presumably surveyed from human autopsy specimens or tissues that were removed because of pathologic conditions not directly involving the organ being examined (5). Human cancers of the lung, breast, and ovary have also been shown to aberrantly overexpress the B7-H4 protein ligand (4,6,7).…”

B7-H4 Expression is Associated with Cancer Progression and Predicts Patient Survival in Human Thyroid Cancer

“…In gastric cancer, B7-H4 significantly correlated with depth of tumor invasion, lymph node metastasis, and overall stage in gastric cancer (Arigami et al, 2010). B7-H4 expression was significantly higher in invasive breast cancer cells and increased B7-H4 expression was associated with negative progesterone receptor status in breast cancer patients (Tringler et al, 2005). Furthermore, the measurement of B7-H4 expression is expected to become a useful tool for the prediction of chemotherapeutic response and prognosis in ovarian cancer patients and gastric cancer patients (Oikonomopoulou et al, 2008;Arigami et al, 2010).…”

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome

“…Despite mRNA expression in various human tissues, immunohistochemistry (IHC) for B7x fails to reveal detectable protein expression in any healthy human organs (23). In stark contrast, aberrant expression of B7x has been observed in cancers of the breast (22,24), lung (16), ovary (22,25), uterus (26), and kidney (27). Thus, B7x, and perhaps B7-H3, have been proposed as potential therapeutic targets in human malignancy.…”