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an energy source for GABAergic BBM cells, leading to suppression of viability and proliferation. Our results
indicate that combinatorial treatment with a GABA agonist and SRC or ERBB2 inhibitors is a potentially
effective therapeutic approach targeting BBM. Finally, consistent with the drug screening data, aberrant Wnt
signaling is a hallmark of many cancers. Dysregulation of canonical and non-canonical Wnt signaling was
reported in triple-negative breast cancer [45-47] . No previous studies have shown any relationship of SIRT and
LRRK2 with HER2+ breast cancer brain metastasis. In conclusion, we have identified both molecular targets
and active clinical/preclinical inhibitors to target breast cancer brain metastasis. In our future studies, we
will evaluate the efficacy of these inhibitors in animal models in vivo.

CONCLUSION
The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of
BBM cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates
BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust
apoptosis in BBM cells. In addition, the finding revealed that agonist-mediated activation of GABA signaling
in combination with inhibition of SRC/ERBB2 signaling acts as an effective strategy to inhibit BBM cell
proliferation. In future studies, we will analyze BBM cell-specific toxicity of the lead candidates alone or in
combinations using larger numbers of BBM, primary breast cancer and glial cell lines. We will identify the
candidates or combination with significantly higher BBM cell selective toxicity for preclinical evaluation
using animal models. In conclusion, the findings of this study provide a rationale for further preclinical
evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target
breast cancer brain metastasis.

DECLARATIONS
Acknowledgments
We tender our heartfelt gratitude to Kerin Higa for critically evaluating and proofreading the manuscript.
We acknowledge Integrative Genomics Core’s sequencing service.

Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Ansari SR, Jandial Z, Wu X, Liu X, Ansari KI
Performed data acquisition, as well as providing administrative, technical, and material support: Ansari SR,
Jandial Z, Chen MY, Ansari KI

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by Department of Defense Breast Cancer Research Program (BC142323); and the
Margaret E. Early Medical Research Trust for experiment design, collection, analysis, and interpretation of
data, and writing of the manuscript.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.