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Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer
Aditi S Khatpe1,2, Adedeji K Adebayo1,2, Christopher A Herodotou1
1Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abstract:
Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.
Insights
Estrogen receptor alpha (ERα) signaling drives many breast cancers. Understanding resistance mechanisms to anti-estrogen therapy, like ERα pathway crosstalk, is key to developing effective combination treatments for recurrent disease.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Estrogen receptor alpha (ERα) and estradiol (E2) signaling are crucial for approximately 70% of breast cancers.
- Anti-estrogen therapies are standard treatments, but resistance leads to recurrence in about 30% of ERα-positive breast cancers, even years after diagnosis.
Purpose of the Study:
- To review the mechanisms of resistance to anti-estrogen therapy in ERα-positive breast cancer.
- To explore the interplay between ERα signaling and other pathways, such as PI3K/AKT/mTOR and cell cycle machinery.
- To highlight how understanding these interactions informs the development of combination therapies.
Main Methods:
- Literature review focusing on ERα signaling, resistance mechanisms, and targeted therapies.
- Analysis of studies investigating ESR1 mutations and pathway crosstalk.
- Examination of clinical data on combination therapies for recurrent breast cancer.
Main Results:
- Resistance to anti-estrogens can arise from ESR1 mutations or crosstalk with growth factor and cell cycle pathways, leading to ligand-independent ERα activation.
- Combination therapies targeting both ERα and these crosstalk pathways (e.g., PI3K/AKT/mTOR or CDK4/6 inhibitors) are clinically utilized for recurrent ERα-positive breast cancer.
Conclusions:
- Understanding the ERα-PI3K/AKT/mTOR pathway nexus is vital for overcoming anti-estrogen resistance.
- Combination strategies targeting ERα and associated signaling networks represent a promising approach for managing recurrent ERα-positive breast cancer.
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