Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

Abstract

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.

A Potential New Mechanism for Bisphenol Molecules to Initiate Breast Cancer through Alteration of Bone Morphogenetic Protein Signaling in Stem Cells and Their Microenvironment

“…Interaction of these isoforms with the BMP signaling elements has not yet being investigated but could be involved in epithelial stem cell response to BMP2. Indeed, the importance of these different ERα isoforms in mammary epithelial SC features and in the context of breast cancer is only just starting to be identified [139,140]. These isoforms can be expressed in both ERα66-positive and -negative cells and display different subcellular localizations [141,142].…”

“…Interestingly, in the context of EDC research, ERα36 displays altered ligand preference and causes distinct effects compared to ERα66. For instance, the tamoxifen drug used as an estrogen antagonist in ERα66 breast cancers behaves as an estrogen agonist for ERα36 [140,144]. Collectively, these different examples illustrate how BMP signaling through its interaction with estrogen signaling is at the crossroad of a number of fundamental physiological processes.…”

Overview of Current Findings about the Role of Oestrogen Receptor α in Cancer Cell Signalling Pathways

“…Exprese ERα36 může být využita pro rozdělení pa cientek do skupin, které budou, či nebudou mít prospěch z léčby TAM. TAM totiž může aktivovat ERα36, čímž podporuje buněčnou proliferaci a rozvoj metastáz [25]. U klinických vzorků rovněž odpovídá exprese ERα36 hladinám ALDH1A1 (aldehyde dehydrogenase 1A1).…”

“…K potlačení těchto efektů TAM autoři navrhují terapii inhibitory ALDH1 nebo protilátkami specifi ckými proti ERα36. Nedávná studie rovněž ukazuje, že exprese ERα36 nemusí být pouze prognostickým bio markerem karcinomu prsu, ale ERα36 se v budoucnu může stát i potenciálním terapeutickým cílem [25].…”

Tamoxifen and ERα36: Fertilizing the seeds of breast cancer metastasis

“…2 In a recent paper in Cell Research, Wang et al add to the evolving story the importance of ERα36 in breast cancer with a report that stimulation of ERα36 promotes metastasis via promotion of ALDH1A1-positive CSCs. 3,4 This group has previously reported that expression of ERα36 is related to resistance to tamoxifen, and that estrogen signaling via ERα36 regulates the maintenance of breast CSCs. 5 In the current study, they analyzed ERα36 expression in 1677 breast cancer samples, and convincingly showed that ERα36 expression was correlated with tumor size, grade, and lymph node involvement.…”