Targeting Semaphorin 7a Signaling in Preclinical Models of Endocrine Therapy-Resistant Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Estrogen receptor-positive (ER+) breast cancer is the most common type and a leading cause of cancer deaths.
• Therapeutic resistance to endocrine therapy is a significant clinical challenge in ER+ breast cancer, leading to recurrence.
• Semaphorin 7a (SEMA7A) is identified as a potential biomarker for poor prognosis and endocrine therapy resistance in ER+ breast cancer.

Purpose of the Study:

• To investigate the mechanisms by which Semaphorin 7a (SEMA7A) contributes to endocrine therapy resistance in ER+ breast cancer.
• To evaluate the therapeutic potential of targeting SEMA7A in ER+ breast cancer models.

Main Methods:

• Investigated SEMA7A protein complex formation with integrins and downstream AKT signaling.
• Utilized mouse models of ER+ breast cancer to test PI3K inhibitors (GCT-007, alpelisib) with tamoxifen.
• Assessed the efficacy of an anti-SEMA7A antibody (SmAbH1) in combination with fulvestrant.

Main Results:

• SEMA7A forms a complex with integrins β1 and β4, activating AKT-mediated prosurvival signaling.
• PI3K inhibitors significantly reduced tumor growth in SEMA7A-expressing ER+ breast cancer mouse models, alone and with tamoxifen.
• Direct inhibition of SEMA7A using SmAbH1 effectively reduced tumor growth and was effective even with standard-of-care fulvestrant.

Conclusions:

• SEMA7A plays a crucial role in promoting endocrine therapy resistance in ER+ breast cancer via integrin-AKT signaling.
• Targeting SEMA7A with PI3K inhibitors or anti-SEMA7A antibodies represents a viable therapeutic strategy.
• Patients with ER+ SEMA7A+ breast tumors are potential candidates for PI3K-targeted or anti-SEMA7A-based therapies.