While triple-negative breast cancer (TNBC) does not express primary estrogen receptor alpha (ERα), estrogen receptor beta (ERβ) expression in 25-30% of TNBC offers a promising opportunity for targeted anticancer therapy. ERβ expression has been identified as an independent predictor of recurrence, metastasis, and mortality and is generally considered a favorable clinical feature in breast cancer. ERβ1 expression, in particular, is associated with a favorable prognosis in TNBC, with reduced relapses and improved survival outcomes. Importantly, the FDA-approved drug for ERα-positive breast cancer tamoxifen is also a ligand for ERβ. ERβ has been suggested to be antiproliferative in nature, mainly based on exogenous overexpression of ERβ cDNA in cancer cell lines.
However, observations in other preclinical studies indicate that ERβ is instead associated with proliferation in mammary epithelial cells,10 breast cancer cells, and TNBC. An important feature of TNBC is the high prevalence (~80%) of mutations in the p53 tumor suppressor gene. Preclinical studies on breast cancer cells have demonstrated that ERβ is able to oppose certain pro-tumorigenic functions of mutant p53. ERβ directly binds and antagonizes p53, and importantly, the status of parent versus mutant p53 has been shown to be a determinant of the pro-cons anti-tumorigenic functional duality of ERβ. Recent molecular investigations have been conducted into how tamoxifen might help patients with triple-negative cancer. The p53 mutant has been found to bind to and inactivate the p73 tumor suppressor when it is not restricted.
ERβ has been shown to bind and sequester mutant p53, resulting in reactivation of p73. Reactivated p73 is free to promote the expression of antitumor genes, including p21) and PUMA, resulting in cell cycle arrest and cell death. In particular, tamoxifen was shown to increase the interaction of mutant p53 with ERβ, possibly because the drug-bound receptor has higher affinity for this anti-oncogenic protein precisely when it is mutated. In the case of brain metastases, estrogens have been shown to reduce the adaptive immune response and phagocytic capacity of microglia, through bias to the M2 phenotype, promoting metastatic growth even in ER-negative disease. Recent mouse models have demonstrated that tamoxifen inhibits M2 polarization and brain tumor progression.
Which suggests it may be an effective treatment for TNBC with brain metastases. The only options for treating brain metastases in triple-negative breast cancer are biologics with cytotoxic load, namely sacituzumab-govitecan and trastuzumab-deruxtecan. Although very effective, they are very expensive and it is not possible to apply them to all patients in all settings. Instead, tamoxifen is very cheap and if further tests confirm that it is effective in limiting the growth of TNBC cells, the chemotherapy arsenal will be able to take into account this molecule which, wrongly, has been excluded from the treatment of triple-negative cancer because it was deemed ineffective given the absence of hormone receptors.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Scientific publications
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Lu C et al. Breast Cancer Res Treatm 2023; 197(1):71-82.
Kadamkulam Syriac A et al. Breast Cancer 2022; 14:1-13.
Bado I, Nicholas F et al. Oncotarget 2016; 7(12):13599–611.