ERĪ±-36 regulates progesterone receptor activity in breast cancer
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Abstract: Background: Alterations in estrogen and progesterone signaling, via their respective receptors, estrogen receptor alpha (ERĪ±) and progesterone receptor (PR), respectively, are largely involved in the development of breast cancer (BC). The recent identification of ERĪ±-36, a splice variant of ERĪ±, has uncovered a new facet of this pathology. Although ERĪ±-36 expression is associated with poor prognosis, metastasis development, and resistance to treatment, its predictive value has so far not been associated with a BC subtype and its mechanisms of action remain understudied. Methods: To study ERĪ±-36 expression in BC specimens, we performed immunochemical experiments. Next, the role of ERĪ±-36 in progesterone signaling was investigated by generating KO clones using the CRISPR/CAS9 technology. PR signaling was also assessed by proximity ligation assay, Western blotting, RT-QPCR, and ChIP experiments. Finally, proliferation assays were performed with the IncuCyte technology and migration experiments using scratch assays. Results: Here, we demonstrate that ERĪ±-36 expression at the plasma membrane is correlated with a reduced disease-free survival in a cohort of 160 BC patients, particularly in PR-positive tumors, suggesting a crosstalk between ERĪ±-36 and PR. Indeed, we show that ERĪ±-36 interacts constitutively with PR in the nucleus of tumor cells. Moreover, it regulates PR expression and phosphorylation on key residues, impacting the biological effects of progesterone. Conclusions: ERĪ±-36 is thus a regulator of PR signaling, interfering with its transcriptional activity and progesterone-induced anti-proliferative effects as well as migratory capacity. Hence, ERĪ±-36 may constitute a new prognostic marker as well as a potential target in PR-positive BC.
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Direction GĆ©nĆ©rale de lāoffre de Soins (none)
Government ivory (none)
Canceroloe CLARA (none)