Abstract
Triple negative breast cancer (TNBC) cells are resistant to hormonal/targeted therapies. This study aims to investigate epigenetic differences between TNBC and other types of breast cancer and the effect of epigenetic modulation on the response of TNBC cells to hormonal therapy. Thus, we investigated (i) the expression of different epigenetic markers, (ii) the effect of epigenetic modifying agents on the expression of ERα and HER2/ERBB2 and (iii) the effect on the response to tamoxifen in four breast cancer cell lines with different hormonal receptor status. Our results revealed a differential expression patterns of epigenetic markers in the four breast cancer cells. In TNBC cells, histone deacetylases (HDAC) 1 and 2 were less expressed, whereas HDACs 4 and 6 were overexpressed. Interestingly, treatment with epigenetic modifiers resulted in (i) a pronounced increase in the expression of ERα and HER2/ERBB2 along with (ii) an increase in the sensitivity of TNBC cells to tamoxifen. Collectively, this study indicates a different epigenetic background for TNBC cells, which represses the expression of ERα and HER2/ERBB2. Furthermore, we provide here the rationale for the use of epigenetic modifiers to enhance the response of TNBC to hormonal therapy through upregulation of ERα.
Highlights
Breast cancer (BC) is a heterogeneous disease, which is subclassified into categories depending on the expression of estrogen and progesterone receptors and the amplification of human epidermal growth factor receptor 2 (HER2/ERBB2) [1]
Estrogen Receptorα (ERα) and HER2/ERBB2 expressions contribute to hormonal therapy response in BC [20,21]
Our results revealed differential expression levels of ERα and HER2/ERBB2 in the four cell lines (Figure 1A,B)
Summary
Breast cancer (BC) is a heterogeneous disease, which is subclassified into categories depending on the expression of estrogen and progesterone receptors and the amplification of human epidermal growth factor receptor 2 (HER2/ERBB2) [1]. Triple negative breast cancer (TNBC) is one subtype that lacks the expression of steroid hormone receptors and HER2/ERBB2 gene amplification or protein overexpression [2]. TNBC is the most heterogeneous type and accounts for 15–20% of all breast cancer cases. It has poor clinical and pathological features and considered more aggressive compared to other. TNBC generally shows partial response to the available drugs because of its aggressive phenotype. Due to the lack of expression of ERα and HER2/ERBB2 amplification/overexpression, TNBC cells normally do not respond to hormonal therapy using drugs such as tamoxifen [5,6,7,8,9].
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