Targeting ERα36: A Promising Strategy for Treating Triple-Negative Breast Cancer

Abstract: Triple-Negative Breast Cancer (TNBC), defined by the lack of Estrogen Receptors (ER), Progesterone Receptors (PR), and human epidermal growth factor receptor 2 (HER2), remains one of the most aggressive and therapeutically challenging subtypes of breast cancer. The absence of these traditional molecular targets limits the effectiveness of conventional hormone and HER2-targeted therapies, necessitating the exploration of alternative therapeutic strategies. Recent attention has shifted toward ER-α36, a structurally distinct isoform of the classical estrogen receptor α (ER-α66), which lacks the AF-1 and AF-2 transactivation domains but retains the ability to mediate nongenomic estrogen signaling. ER-α36 is implicated in activating critical oncogenic pathways, including EGFR/Src/ERK, MAPK/ERK, and PI3K/AKT/mTOR, all of which contribute to enhanced proliferation, survival, and metastasis in TNBC. Therapeutic approaches targeting these downstream signaling cascades have shown promise in preclinical and early clinical studies. Notably, combinations such as pan-PI3K inhibitors with fulvestrant, and agents like BYL719 (alpelisib) and AZD5363 (capivasertib) with chemotherapeutics like docetaxel, have demonstrated significant antitumor efficacy. Additionally, monoclonal antibodies such as trastuzumab and seribantumab have been found to selectively inhibit components of the MAPK/ERK and PI3K/AKT pathways, respectively, offering further avenues for targeted intervention. Moreover, tyrosine kinase inhibitors that disrupt EGFR signaling are emerging as valuable tools to suppress cancer cell viability and proliferation. This review highlights ER-α36 not only as a key player in the molecular pathology of TNBC but also as a promising therapeutic target. By focusing on ER-α36-mediated signaling mechanisms, researchers and clinicians may develop more effective, personalized strategies for treating TNBC. Targeting ER-α36 and its associated pathways represents a forward-looking approach that could address the pressing need for novel therapies in this difficult-to-treat breast cancer subtype.