FOXC1 identifies basal-like breast cancer in a hereditary breast cancer cohort.

Jeff Johnson,Xiaojiang Cui,Xiao Zhang,Yi Yu-Rice,Clive Taylor,Michael Choi,Bingchen Han,Armando E Giuliano,Ying Qu,Farin Amersi,Farnaz Dadmanesh,Sanjay Bagaria

doi:10.18632/oncotarget.12370

Jeff Johnson, Xiaojiang Cui + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.12370

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Abstract

Breast cancers arising in the setting of the hereditary breast cancer genes BRCA1 and BRCA2 are most commonly classified as basal-like breast cancer (BLBC) or luminal breast cancer, respectively. BLBC is an aggressive subtype of breast cancer associated with liver and lung metastases and poorer prognosis than other subtypes and for which chemotherapy is the only systemic therapy. Multiple immunohistochemical markers are used to identify the basal-like subtype, including the absence of estrogen receptor alpha, progesterone receptor, and human epidermal growth factor receptor 2. Forkhead box C1 (FOXC1) has been identified as a specific marker expressed in BLBC in general breast cancer cohorts. We examined an institutional cohort of breast cancer patients with germline BRCA1 (n=46) and BRCA2 (n=35) mutations and found that FOXC1 expression on immunohistochemical staining is associated with BRCA1 vs BRCA2 mutations [30/46 vs. 6/35]. In BRCA1 mutant tumors, FOXC1 was expressed in 28/31 BLBC tumors and 2/13 non-BLBC tumors, In BRCA2 mutant tumors, FOXC1 was expressed in 5/5 BLBC tumors and 1/30 non-BLBC tumors. In cell culture models of BRCA1-mutant breast cancer, FOXC1 is associated with increased proliferation and may serve as a marker for sensitivity to PARP-inhibitor therapy with olaparib.

Highlights

Gene expression profiling with unsupervised clustering analysis has demonstrated distinct classes within the molecular heterogeneity of breast cancers
No significant differences were seen in the rates of distant metastases, distant recurrence, disease-free survival, or overall survival, a trend was seen towards increased locoregional recurrence in Forkhead box C1 (FOXC1)+ tumors (p=0.0512) (Supplementary Table S1)
We have demonstrated that FOXC1 can identify BRCA1-mutant basal-like breast cancer (BLBC) cancer

Summary

Introduction

Gene expression profiling with unsupervised clustering analysis has demonstrated distinct classes within the molecular heterogeneity of breast cancers. Hereditary breast cancer arising in the setting of germline mutations in BRCA1 and BRCA2 is recognized to generally sort with the BLBC and luminal subtypes of breast cancer, respectively [3, 4] While these molecular subtypes are defined by clustering analysis of gene expression profiles, in clinical practice these molecular subtypes are approximated by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In this classification system, tumors expressing estrogen receptor α (ERα) and/or progesterone receptor (PR) with low Ki-67 are categorized as luminal A; ER+ and/or PR+ with high Ki-67 or HER2+ are categorized as luminal B; ER-, PR-, and Her2+ by FISH are categorized as Her2+; and tumors lacking expression of these markers (ER-PR-HER2-) are “triple-negative” and categorized as BLBC [5]. BLBC, which lacks ERα and HER2, has no recognized targeted therapy and has a relatively poor prognosis

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