PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine...

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Preclinical and clinical data link PI3K/AKT/mTOR pathway activation to acquired endocrine therapy resistance in breast cancer.
• Estrogen receptor α (ERα)-positive breast cancer is a significant clinical challenge, often developing resistance to hormonal treatments.

Purpose of the Study:

• To investigate differences in PI3K/AKT/mTOR pathway activation between primary and metastatic ERα-positive breast cancer tissues.
• To determine the association between adjuvant endocrine therapy and the activation of key downstream proteins in this pathway.

Main Methods:

• Immunohistochemistry was used to assess the expression of phosphorylated mTOR (p-mTOR), phosphorylated 4E-Binding Protein 1 (p-4EBP1), and phosphorylated p70S6K (p-p70S6K).
• Expression levels were quantified by scoring the proportion of immunostained tumor cells and cytoplasmic intensity.
• Statistical analyses, including multivariate analysis, were performed to evaluate the association with adjuvant endocrine therapy.

Main Results:

• Adjuvant endocrine therapy was associated with increased p-mTOR expression in metastatic lesions compared to primary tumors (median difference 45%).
• Similar increases were observed for p-4EBP1 and p-p70S6K expression in patients who received endocrine therapy.
• Multivariate analyses confirmed a significant association between adjuvant endocrine therapy and increased activation of p-mTOR, p-4EBP1, and p-p70S6K.

Conclusions:

• Compensatory activation of the PI3K/AKT/mTOR pathway is a clinically relevant mechanism contributing to acquired endocrine therapy resistance in breast cancer.
• Targeting the PI3K/AKT/mTOR pathway may represent a therapeutic strategy to overcome endocrine resistance.
• Understanding these molecular alterations is crucial for developing more effective breast cancer treatments.