Estrogen receptor variant ERα46 and insulin receptor drive in primary breast cancer cells growth effects and interleukin 11 induction prompting the motility of cancer-associated fibroblasts.

Abstract

Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild-type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC-1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC-1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high-throughput RNA sequencing analysis, we have also found that the cytokine interleukin-11 (IL11) is the main factor linking BCAHC-1 cells to breast cancer-associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC-1 cells regulates pro-tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM-1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC.

• Authors: Francesca Cirillo, Michele Pellegrino, Marianna Talia, Ida Daniela Perrotta, Damiano Cosimo Rigiracciolo, Asia Spinelli, Domenica Scordamaglia, Lucia Muglia, Rita Guzzi, Anna Maria Miglietta, Ernestina Marianna De Francesco, Antonino Belfiore, Marcello Maggiolini, Rosamaria Lappano
• Journal: Clinical and translational medicine (Clin Transl Med) Vol. 11 Issue 11 Pg. e516 (11 2021) ISSN: 2001-1326 [Electronic] United States
• PMID: 34841688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• IL11 protein, human
• Interleukin-11
• Receptor, Insulin

Topics

• Breast Neoplasms (drug therapy)
• Cancer-Associated Fibroblasts (metabolism)
• Cell Movement (drug effects)
• Estrogen Receptor alpha (metabolism, therapeutic use)
• Female
• Gene Expression Profiling
• Humans
• Interleukin-11 (pharmacology, therapeutic use)
• Middle Aged
• Receptor, Insulin (pharmacology, therapeutic use)
• Signal Transduction (drug effects)