Abstract
Triple Negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2. TNBC accounts for 15-20% of all breast cancer cases but accounts for over 50% of mortality. We propose that Estrogen receptor-beta (ERβ) and IGF2 play a significant role in the pathogenesis of TNBCs, and could be important targets for future therapy.Tissue microarrays (TMAs) from over 250 TNBC patients' were analyzed for ERβ and IGF2 expression by immunohistochemistry. Expression was correlated with clinical outcomes. In addition, TNBC cell lines Caucasians (CA): MB-231/BT549 and African Americans (AAs): MB-468/HCC70/HCC1806 were used to investigate the effect of hormonal and growth factor regulation on cell proliferation.TMAs from AAs had higher expression of ERβ and IGF2 expression when compared to CA. ERβ and IGF2 were found to be upregulated in our TNBC cell lines when compared to other cell types. TNBC cells treated with ERβ agonist displayed significant increase in cell proliferation and migration when compared to controls. AA tissue samples from TNBC patients had higher expression of ERβ. African-American breast cancer TNBC tissue samples from TNBC patients have higher expression of ERβ. In addition, TNBC cell lines were also found to express high levels of ERβ. IGF2 increased transcription of ERβ in TNBC cells. Understanding the mechanisms of IGF2/ERβ axis in TNBC tumors could provide an opportunity to target this aggressive subtype of breast cancer.
Highlights
Triple negative breast cancer (TNBC) is a subtype of breast cancer (BC) and is defined by the lack of expression of three receptors: the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) [1]
A database was established using mRNA expression data downloaded from gene expression omnibus (GEO), the cancer genome Atlas (TCGA), European genome-phenome archive (EGA), and PubMed repositories to identify datasets with published mRNA expression and clinical data
When patients were given chemotherapy as a whole (Figure 1B) or adjuvant chemotherapy (Figure 1C), high ERβ expression is significantly correlated with lower relapse free survival (RFS) (P = 0.0315 and 0.0415 respectively) and a trend with high ERβ expression is seen to coincide with lower distance metastasis free survival
Summary
Triple negative breast cancer (TNBC) is a subtype of breast cancer (BC) and is defined by the lack of expression of three receptors: the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) [1]. Current endocrine and HER2-targeted therapies are not viable for TNBCs, and the only treatment option available is chemotherapy [2, 4,5,6]. TNBC patients tend www.oncotarget.com to have higher clinical response rates to chemotherapy, they have higher rates of distant recurrence and a worse overall prognosis than women with other breast cancer subtypes [7, 8]. Finding a new molecular target and/or treatment is the upmost importance within this patient population and in women with breast cancer in general
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