Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Augusto, TV (Author) Other; Amaral, C (Author) Other; Almeida, CF (Author) Other; Teixeira, N (Author) Other; Georgina Correia da Silva (Author) FFUP

Journal

Title: Molecular and Cellular Endocrinology

Vol. 537

ISSN: 0303-7207

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 9 Citations

Other information

Authenticus ID: P-00V-J45

DOI: 10.1016/j.mce.2021.111426

Abstract (EN): Estrogen receptor-positive (ER+) breast carcinomas are the most common subtype, corresponding to 60% of the cases in premenopausal and 75% in postmenopausal women. The third-generation of aromatase inhibitors (AIs), the non-steroidal Anastrozole (Ana) and Letrozole (Let) and the steroidal Exemestane (Exe), are considered a first-line endocrine therapy for postmenopausal women. Despite their clinical success, the development of resistance is the major setback in clinical practice. Nevertheless, the lack of cross-resistance between AIs hints that these drugs may act through distinct mechanisms. Therefore, this work studied the different effects induced by AIs on biological processes, such as cell proliferation, death, autophagy and senescence. Moreover, their effects on the regulation of the hormonal environment were also explored. The non-steroidal AIs induce senescence, through increased YPEL3 expression, on aromatase-overexpressing breast cancer cells (MCF-7aro), whereas Exe promotes a cytoprotective autophagy, thus blocking senescence induction. In addition, in a hormone-enriched environment, the non-steroidal AIs prevent estrogen signaling, despite up-regulating the estrogen receptor alpha (ER alpha), while Exe down-regulates ER alpha and maintains its activation. In these conditions, all AIs up-regulate the androgen receptor (AR) which blocks EGR3 transcription in Exe-treated cells. On the other hand, in hormone-depleted conditions, a crosstalk between AR and ER alpha occurs, enhancing the estrogenic effects of Exe. This indicates that Exe modulates both ER alpha and AR, while Ana and Let act as pure AIs. Thus, this study highlights the potential clinical benefit of combining AR antagonists with Exe and discourages the sequential use of Exe as second-line therapy in postmenopausal breast cancer.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15