Friday, April 19, 2024
4/19/2024
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.
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