Bcl-2 Is Infrequently Upregulated in Metastatic Breast Carcinomas
AP Subhawong, DW Molavi, MK Halushka, H Nassar, R Vang, S Sukumar, P Argani. The Johns Hopkins Hospital, Baltimore, MD
Background: Bcl2 is an antiapoptotic protein which promotes cell survival. Bcl2 is expressed in normal breast epithelium, and in breast cancer its expression correlates with estrogen receptor (ER) positivity. In vitro data suggests that Bcl2 promotes chemoresistance (J Surg Res 1998; 76:22-26 and Endocr Relat Cancer 2000; 7:237-269) and is upregulated in metastatic breast carcinoma (MBC) (Clin Exp Metastasis 2005; 22:59-67). A direct and comprehensive comparison of Bcl2 expression between multiple distant metastases and their paired primary breast carcinomas (PBCs) has not been performed.
Design: We performed rapid autopsies (postmortem interval, 1-4 hours) on 15 consenting patients with MBC. Single-patient tissue microarrays (TMAs) were constructed from the patient's archived PBC and multiple different MBCs harvested at autopsy. TMAs were labeled by immunohistochemistry (IHC) for ER, progesterone receptor (PR), HER-2, and CK5/6 to determine the PBCs' IHC surrogate profile corresponding to breast cancer subcategories defined by gene expression profiling. TMAs were labeled for Bcl2 and expression in PBC (145 spots from 15 cases) and matched MBC (778 spots from 180 different MBCs) were compared.
Results: There were 8 ER+, HER-2- (Luminal A) cases; 5 ER-, PR-, HER-2-, CK5/6+ (Basal-like) cases; 1 ER+, HER-2+ (Luminal B) case; and 1 ER-, PR-, and HER-2+ (HER-2) case. All 9 ER+ cases (8 Luminal A, 1 Luminal B) showed Bcl2 expression in the PBC, while none of the 6 ER- cases (5 Basal-like, 1 HER-2) did (p<0.001). Four Luminal A cases lost expression of ER and/or PR in their MBC; 2 of these demonstrated downregulation of Bcl2 in their MBC; in the other 2 Bcl2 expression was retained. Of the 4 Luminal A cases which remained ER positive in their MBC, 2 maintained Bcl2 expression in their MBC, one lost Bcl2 expression in its MBC, while in one Bcl2 was upregulated in a subset of MBC showing increased PR expression. Of the 6 ER- cases, 3 remained Bcl2 negative in all MBC, while 3 demonstrated focal upregulation in a minority of MBC. The Luminal B case retained weak ER labeling and Bcl2 expression in its MBC.
Conclusions: Bcl2 is uncommonly and inconsistently overexpressed in MBC. Instead, downregulation of Bcl2 expression may occur in the setting of hormone therapy resistance. Since Bcl2 may paradoxically inhibit cell growth in some solid tumors, we hypothesize that downregulation of Bcl2 may promote MBC growth. Our findings call into question the utility of potential anti-Bcl2 targeted therapy in MBC.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 52, Monday Morning