Estrogen receptor-beta is a potential target for triple negative breast cancer treatment

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.

Trifolium pratense L. (red clover) extract and doxorubicin synergistically inhibits proliferation of 4T1 breast cancer in tumor‐bearing BALB/c mice through modulation of apoptosis and increase antioxidant and anti‐inflammatory related pathways

“…Studies have shown that isoflavones preferentially bind to and transactivate ERβ rather than ERα, which induces conformational changes in the receptor. Austin et al (2018) showed that ERβ could be targeted by isoflavone compounds in TNBC tumors (Austin et al., 2018). In a randomized placebo‐controlled clinical trial on postmenopausal women, Palomares et al.…”

The role of estrogen receptor beta in breast cancer

“…In contrast, ERβ1 was found to be associated with significantly worse 5-year OS in TNBC patients [55]. Moreover, a study indicated that patients with TNBC and positive ERβ expression exhibited poorer DFS [54] and decreased recurrence-free survival (RFS) regardless of chemotherapy use [51].…”

Mechanisms linking the renin-angiotensin system, obesity, and breast cancer

“…Adiponectin is responsible for switching macrophages from the M1 to M2 phenotype, thus improving the inflammatory profile (Li et al 2011). By contrast, human BC cells express adiponectin receptors (AdipoR1, R2), which, when present at low concentrations can promote ER+ BC proliferation, but reduce triple-negative breast cancer cell (TNBC) growth in the presence of 17-β estradiol (Dieudonne et al 2006, Pfeiler et al 2008, Austin et al 2018. This can be explained by the downstream signaling crosstalk between adiponectin and estrogen receptors in modulating AMPK and MAPK pathways respectively in TNBC and ER+ BC cells (Gelsomino et al 2019).…”