What does this research mean for the field?

GPER signaling modulates endocrine therapy sensitivity in PIK3CA-mutant HR+ advanced breast cancer and could serve as a novel biomarker for personalized treatment. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

Investigate how GPER signaling affects endocrine therapy sensitivity in PIK3CA-mutant HR+ advanced breast cancer.

February 19, 2026

Abstract PS4-02-26: Gper signaling as a biomarker for endocrine therapy sensitivity in pik3ca mutant hr+ advanced breast cancer

Key Points

Investigate how GPER signaling affects endocrine therapy sensitivity in PIK3CA-mutant HR+ advanced breast cancer.
Identified PIK3CA-mutant cell lines MCF-7 and T47D.
Developed resistance models for tamoxifen and palbociclib.
Measured GPER expression and ABCG2 efflux pump activity with quantitative PCR and Western blot.
Assessed antiproliferative effects using MTT assays and flow cytometry.
Performed siRNA knockdown of GPER/ABCG2 to evaluate therapy response.
GPER expression increased in tamoxifen and palbociclib-resistant cell lines.
Combinations of inavolisib with abemaciclib or ribociclib showed superior effects over palbociclib.
Knockdown of GPER/ABCG2 improved sensitivity to multiple therapies and reduced tumor growth.

Abstract

Abstract The INAVO 120 clinical trial confirmed the efficacy of first-line palbociclib combined with inavolisib in hormone receptor-positive (HR+) advanced breast cancer patients harboring PIK3CA mutations who developed resistance to adjuvant endocrine therapy. However, the comparative effectiveness of alternative CDK4/6 inhibitors (e.g., abemaciclib, ribociclib) in the first line setting, or the potential of crossline therapy (using abemaciclib or ribociclib combined with inavolisib) following palbociclib resistance in PIK3CA-mutant patients remains unclear. Our prior research identified the G protein-coupled estrogen receptor (GPER) as a pivotal initiator of endocrine resistance in HR+ advanced breast cancer, further driving activation of the PI3K/AKT/mTOR (PAM) signaling pathway. We infer that GPER signaling modulates endocrine therapy sensitivity in PIK3CA-mutant HR+ advanced breast cancer and could serve as a novel biomarker to guide personalized clinical treatment decisions. To demonstrate this hypothesis, we identified MCF-7 (E545K-mutant) and T47D (H1047R-mutant) breast cancer cell lines harboring PIK3CA mutations, and developed tamoxifen-resistant (MCF-7/TAM-R, T47D/TAM-R) and palbociclib-resistant (MCF-7/Palb-R, T47D/Palb-R) models to recapitulate first- and second-line endocrine resistance in clinic. Interestingly, GPER expression was significantly upregulated in all above resistant cell lines and promoting ABCG2 efflux pump expression via the GPER/PI3K/AKT pathway, as validated by quantitative PCR and Western blot. In GPERhigh tamoxifen-resistant cells, combinations of inavolisib with abemaciclib or ribociclib exhibited superior antiproliferative effects compared to palbociclib-based regimens, which assessed by MTT assays, flow cytometry for apoptosis, and cell cycle analysis. Knockdown of GPER/ABCG2 axis using siRNA normalized the efficacy of palbociclib, abemaciclib, and ribociclib in combination with inavolisib, underscoring GPER’s critical role in diverse CDK4/6 inhibitors sensitivity. Notably, in palbociclib-resistant cells, combinations of inavolisib with abemaciclib or ribociclib significantly outperformed inavolisib monotherapy. Furthermore, GPER/ABCG2 knockdown not only partially reversed palbociclib resistance, but also enhanced sensitivity to abemaciclib- and ribociclib-based regimens, demonstrating reduced tumor growth and improved therapeutic response upon GPER signaling inhibition. Therefore, assessing GPER signaling activation in tumor biopsies may enable precise identification of PIK3CA-mutant HR+ advanced breast cancer patients likely to benefit from specific endocrine and targeted therapy combinations. Integrating PI3K, CDK4/6, and GPER-targeted therapies represents a promising strategy to overcome endocrine resistance in the future, offering a path toward personalized treatment paradigms with improved clinical outcomes. Citation Format: X. ZengZ. SunQ. HuM. TangC. LiuZ. LiuT. Yu. Gper signaling as a biomarker for endocrine therapy sensitivity in pik3ca mutant hr+ advanced breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-26.

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