Memon Zaida

Background:  Breast cancer remains a leading cause of cancer-related mortality in women, and resistance to therapy is a key driver of poor outcomes in aggressive subtypes such as HER2-positive (HER2+) and triple-negative breast cancer (TNBC). HER2+ tumors often initially respond to trastuzumab, but develop secondary resistance due to activation of downstream survival pathways. TNBC, lacking estrogen, progesterone, and HER2 receptors, has limited treatment options and frequently metastasizes. Despite their molecular differences, emerging evidence suggests these subtypes may converge functionally on key oncogenic signaling pathways, creating potential for cross-subtype therapeutic strategies.

Objective:  To evaluate how PIK3CA, NRAS, and RHBDL2 promote resistance, stemness, and progression in HER2+ and TNBC, and to identify shared pathway vulnerabilities that may guide combinatorial therapy strategies.

Search Methods:  Literature was sourced using PubMed and Google Scholar from 2017-2024. Keywords included: “PIK3CA breast cancer,” “trastuzumab resistance,” “NRAS TNBC,” “RHBDL2 dormancy,” “NF-κB breast cancer,” and “functional diagnostics in oncology.” Emphasis was placed on five primary peer-reviewed research articles used in the associated presentation.

Results:  In HER2+ disease, mutations in PIK3CA drive constitutive PI3K/AKT/mTOR signaling, bypassing HER2 inhibition and leading to trastuzumab resistance. The PC-B-142CA cell line, derived from a HER2+/PIK3CA+ tumor, displayed this resistant phenotype, consistent with clinical data from Seo et al, which showed PIK3CA-mutated tumors had lower pathologic complete response rates and shorter disease-free survival.² In TNBC, NRAS mutations activated NF-κB signaling via PTPN20, enhancing migratory and invasive potential in the PC-B-148CA model.³ Another mechanism in TNBC involved the membrane protease RHBDL2, which reactivated dormant cells via the YAP1 → USP31 → NF-κB axis, promoting cancer stem cell (CSC) reprogramming and relapse.⁴  Despite these distinct genetic drivers, both HER2+ and TNBC subtypes exhibited functional convergence on the PI3K and NF-κB signaling axes. Data from Zhang et al demonstrated that pathway activity did not always correlate with mutation status, highlighting the limitations of genomics alone for clinical decision-making.⁵ Instead, transcriptomic and proteomic analyses offered more accurate predictions of therapeutic response. These findings support a shift toward multi-pathway targeted therapy and functional diagnostics to guide treatment decisions, rather than relying solely on receptor status or mutation profiling.

Conclusion:  This review highlights shared vulnerabilities between HER2+ and TNBC and proposes a unified mechanistic framework in which PI3K, NF-κB, and CSC programs sustain resistance and progression. These insights support the development of combinatorial therapeutic strategies (e.g., PI3K + NF-κB inhibition) and underline the value of functional tumor profiling in precision oncology.

Work Cited:

1. Thongchot S, Daduang J, Seubwai W, et al. Establishment and characterization of two novel breast cancer cell lines derived from HER2-positive and triple-negative breast cancer patients. Oncol Rep. 2021;46(6):254.
2. Seo AN, Jin Y, Park IA, et al. PIK3CA mutations in HER2-positive breast cancers: correlation with pathologic complete response and survival. J Breast Cancer. 2018;21(4):403–411.
3. Zuo X, Hu Z, Li Y, et al. PTPN20-mediated NF-κB activation promotes metastasis in triple-negative breast cancer. Breast Cancer Res. 2024;26:155.
4. Qiao Y, Jiang X, Lee J, et al. RHBDL2 reprograms dormancy in breast cancer via YAP1 and NF-κB activation. eLife. 2021;10:e65418.
5. Zhang B, Wang J, Wang X, et al. Integrated proteogenomic characterization of human high-grade serous ovarian cancer. Cancer Cell. 2017;31(6):820–832.e3.