GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer

Abstract

GPR30 is a novel G protein-coupled estrogen receptor (ER) associated with metastases in breast cancer (BC) and poor survival in endometrial and ovarian tumors. The association of GPR30 expression with inflammatory breast cancer (IBC), an aggressive and commonly hormone-independent form of BC, has not been studied. GPR30, ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), and HER-2 expression were assessed by immunohistochemistry (and FISH for HER-2) in 88 primary IBCs. GPR30 expression was correlated with patient overall survival (OS), disease-free survival (DFS), pathologic variables, and other biomarkers. GPR30 expression was found in 69% of IBC cases. ER, PR, HER-2, and EGFR were found in 43, 35, 39, and 34% of IBC cases, respectively. GPR30 expression correlated inversely with ER expression (P = 0.02). Co-expression of ER and GPR30 was found in 24% of IBC samples; 19% expressed only ER and 46% expressed only GPR30. Univariate analysis showed no association between GPR30 expression and OS or DFS. However, co-expression of ER and GPR30 was associated with improved OS (P < 0.03) and marginally with DFS (P < 0.06); the absence of both ER and GPR30 was associated with worse OS and DFS (P = 0.03 for both). Multivariate analysis identified ER as an independent prognostic factor of OS (P = 0.008) and DFS (P = 0.02). The majority of IBC tumors are GPR30-positive, suggesting that estrogen signaling may be active in ER-negative IBC patients. These findings suggest potential new therapeutic targets for IBC such as novel endocrine agents or direct modulation of GPR30.

Figure 1

Kaplan-Meier survival curves of OS (continuous line) and DFS (dotted line).

Figure 2

Representative IHC for GPR30 expression in IBC samples. Normal breast with negative (A) and strong (B) GPR30 expression. IBC cases with negative (D), moderate (E), and strong (F) GPR30 expression. Placenta (C) was used as a positive control and the inset depicts the negative control. Slides were scanned and digitized using the Aperio digital system (Vista, CA) (20X).

Figure 3

Kaplan-Meier survival curves of OS (A) and DFS (B) time according to GPR30 expression. Dotted line represents GPR30-positive cases; continuous line, GPR30-negative IBC cases.