# Mechanisms of Annexin A6 Mediated Basal-like Breast Cancer Progression

> **NIH NIH SC1** · MEHARRY MEDICAL COLLEGE · 2021 · $363,750

## Abstract

Project Summary
Triple negative breast cancer (TNBC) remains a complex unmet medical need because of its heterogeneity, poor
prognosis, and its potential to grow rapidly and/or metastasize especially following therapeutic intervention. The
response of TNBCs to various therapeutic interventions including tyrosine kinase inhibitors (TKIs) is generally
poor. Our published and ongoing studies have implicated the Ca2+ dependent membrane binding Annexin A6
(AnxA6) in a wide range of cellular functions including cell growth and motility that define tumor progression,
metastasis and chemo-resistance. We have now shown that AnxA6 is a tumor suppressor in TNBC and that the
pro-tumorigenic properties of low AnxA6 and the pro-invasive functions of high AnxA6 TNBC cells are mediated
at least in part, by AnxA6 modulated Ca2+ influx and activation of GRF2. Chronic treatment of AnxA6-low but
not AnxA6 high TNBC cells with TKIs leads to AnxA6 upregulation and accumulation of cholesterol in late
endosomes as a novel mechanism for acquired resistance of AnxA6 low TNBCs to these drugs. Furthermore,
reduced expression of AnxA6 is more relevant in TNBC compared to non-TNBC and may be used as a reliable
biomarker for response to chemotherapy and as an independent predictor of TNBC relapse after chemotherapy.
Interestingly, the reciprocal expression of AnxA6 and GRF2 is clinically relevant and semi-quantitative
assessment of the ratio of GRF2:AnxA6 can be used to delineate rapidly growing from highly invasive TNBCs.
Together, this suggests that AnxA6 plays a critical role in TNBC progression, metastasis and resistance to
therapeutic interventions, but the mechanisms underlying the chronic TKI induced reactivation and the pro-
invasive properties of AnxA6 in TNBC remain poorly understood. We hypothesize that the pro-invasive properties
of AnxA6 are mediated by extracellular and/or intracellular pools of AnxA6 via AnxA6-modulated interaction of
GRF2 with Rho GTPases; and that reactivation of AnxA6 expression is triggered by inhibition of Ca2+ mobilizing
RTKs via potent inhibition of Ca2+ entry channels and/or modification of specific histone marks. To test this we
will determine the mechanisms underlying TKI-induced reactivation of AnxA6 and the effects of AnxA6
reactivation in TNBC progression and metastasis in Aim 1; and in Aim 2, we will determine the mechanisms
underlying the pro-invasive properties of AnxA6 in basal-like TNBC. Data from this study will lead to a better
understanding of how TNBC cells circumvent the effects of chronic treatment with TKIs to become even more
aggressive and/or invasive, key attributes associated with TNBC patient mortality.

## Key facts

- **NIH application ID:** 10090247
- **Project number:** 9SC1GM139814-05
- **Recipient organization:** MEHARRY MEDICAL COLLEGE
- **Principal Investigator:** Amos Malle Sakwe
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $363,750
- **Award type:** 9
- **Project period:** 2021-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090247

## Citation

> US National Institutes of Health, RePORTER application 10090247, Mechanisms of Annexin A6 Mediated Basal-like Breast Cancer Progression (9SC1GM139814-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10090247. Licensed CC0.

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