Reconsidering Aromatase for Breast Cancer Treatment: New Roles for an Old Target

Caciolla, Jessica; Bisi, Alessandra; Belluti, Federica; Rampa, Angela; Gobbi, Silvia

doi:10.3390/molecules25225351

Cited by 24 publications

(16 citation statements)

References 67 publications

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“…The expression of a third marker, the progesterone receptor (PR, NR3C3), an ERα target gene, reflects active estrogenic signaling and is a marker of improved prognosis compared to PR-negative tumors [ 3 ]. ER+ and/or PR+ tumors represent more than two-thirds of breast cancer cases and are currently treated with hormonal therapies that most commonly include aromatase inhibitors, which suppress endogenous estrogen production, or antiestrogens, which compete with estrogens for binding to estrogen receptors and inactivate them by inducing alternative conformations of their ligand-binding domains [ 4 , 5 ]. On the other hand, primary tumors with undetectable ER expression levels and activity are intrinsically resistant to hormonal therapies.…”

Section: Introductionmentioning

confidence: 99%

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Porras

Ismail

Mader

2021

Cells

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Estrogen receptor alpha (ERα, NR3A1) contributes through its expression in different tissues to a spectrum of physiological processes, including reproductive system development and physiology, bone mass maintenance, as well as cardiovascular and central nervous system functions. It is also one of the main drivers of tumorigenesis in breast and uterine cancer and can be targeted by several types of hormonal therapies. ERα is expressed in a subset of luminal cells corresponding to less than 10% of normal mammary epithelial cells and in over 70% of breast tumors (ER+ tumors), but the basis for its selective expression in normal or cancer tissues remains incompletely understood. The mapping of alternative promoters and regulatory elements has delineated the complex genomic structure of the ESR1 gene and shed light on the mechanistic basis for the tissue-specific regulation of ESR1 expression. However, much remains to be uncovered to better understand how ESR1 expression is regulated in breast cancer. This review recapitulates the current body of knowledge on the structure of the ESR1 gene and the complex mechanisms controlling its expression in breast tumors. In particular, we discuss the impact of genetic alterations, chromatin modifications, and enhanced expression of other luminal transcription regulators on ESR1 expression in tumor cells.

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Section: Introductionmentioning

confidence: 99%

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Porras

Ismail

Mader

2021

Cells

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“…However, some studies have not demonstrated significant differences in markers of bone turnover between exemestane, anastrozole, and letrozole arms ( 127 ). There is evidence that exemestane use results in less BMD loss compared to letrozole and anastrozole at 24 months of therapy ( 128 , 129 ), though it remains to be seen if fewer patients on exemestane develop fractures. The MA.27 trial comparing exemestane with anastrozole in the adjuvant setting identified less reported osteoporosis in patients randomized to exemestane, 31% vs 35% in the exemestane and the anastrozole arm (p=0.001), respectively ( 130 ), however further analysis within the MA.27 cohort showed no significant differences in BMD between exemestane and anastrozole at 24 months ( 130 ).…”

Section: Manifestations Of Aimssmentioning

confidence: 99%

“…With greater understanding of the mechanisms of AIMSS, HR+ breast cancer therapies with fewer musculoskeletal symptoms can be developed. Advancements in pharmacologic research increase optimism for the design of more tolerable therapies targeting aromatase that spare musculoskeletal tissues from toxicities of estrogen deprivation ( 128 , 132 ).…”

Section: Manifestations Of Aimssmentioning

confidence: 99%

Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management

et al. 2021

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Aromatase inhibitors (AIs) are a key component in the chemoprevention and treatment of hormone receptor-positive (HR+) breast cancer. While the addition of AI therapy has improved cancer-related outcomes in the management of HR+ breast cancer, AIs are associated with musculoskeletal adverse effects known as the aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) that limit its tolerability and use. AIMSS is mainly comprised of AI-associated bone loss and arthralgias that affect up to half of women on AI therapy and detrimentally impact patient quality of life and treatment adherence. The pathophysiology of AIMSS is not fully understood though has been proposed to be related to estrogen deprivation within the musculoskeletal and nervous systems. This review aims to characterize the prevalence, risk factors, and clinical features of AIMSS, and explore the syndrome’s underlying mechanisms and management strategies.

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“…Due to its key role in estrogens’ biosynthesis, aromatase has been recognized as a crucial target in hormone-dependent cancers [ 68 ]. Despite being highly effective, aromatase inhibitors generally lead to cardiovascular events increase and bone density reduction [ 69 ]. Moreover, selective estrogen receptors modulators, which mainly represent the alternative therapeutic approach in these tumors, have shown additional issues in long-term therapies, such as increased risk of endometrial cancer and drug resistance [ 70 ].…”

Section: The Interplay Between Metabolism and Cancer: Unexplored Targets And Future Challenges Within Adiporonmentioning

confidence: 99%

AdipoRon and Other Adiponectin Receptor Agonists as Potential Candidates in Cancer Treatments

Nigro

Daniele

Salzillo

et al. 2021

IJMS

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The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as “the real 21st-century disease”. Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.

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Reconsidering Aromatase for Breast Cancer Treatment: New Roles for an Old Target

Cited by 24 publications

References 67 publications

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Positive Regulation of Estrogen Receptor Alpha in Breast Tumorigenesis

Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management

AdipoRon and Other Adiponectin Receptor Agonists as Potential Candidates in Cancer Treatments

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