Investigating the functional significance of AKTIP loss in breast cancer

Abstract

Endocrine therapy is an effective treatment for estrogen receptor α (ERα)-positive breast cancer patients. However, the therapeutic efficacy of endocrine therapy is greatly hampered by the emergence of endocrine resistance. Strategies to overcome endocrine resistance are therefore imperative to improve the survival outcomes of ERα-positive breast cancer patients.

AKT interacting protein (AKTIP) was first identified as a binding partner of AKT which is a key signaling molecule along the PI3K signaling pathway. While copy number loss of AKTIP is frequently observed in a number of malignancies, including breast cancer, its functional roles in cancer remain largely unexplored. In breast cancer, copy number loss of AKTIP is enriched in the ERα-positive subtype and low AKTIP mRNA level correlates with poor patient survivals in this subtype, suggesting that AKTIP loss may be selected in this group of patients for functional advantages. The aims of this study are to investigate the cell biology, downstream signaling and therapeutic implications of AKTIP loss in breast cancer, and to examine whether these functional impacts are manifested in a subtype-dependent manner.

Here, I demonstrated that AKTIP acts as a tumor suppressor gene in ERα-positive breast cancer. In contrast to the previously reported role of AKTIP in AKT signaling, AKTIP did not bind AKT and the loss of AKTIP had no significant impact on AKT signaling in breast cancer cells. Loss of AKTIP promoted the acquisition of malignant phenotypes in ERα-positive cells through the activation of ERα and JAK2/STAT3 signaling pathways. Inhibition of ERα ubiquitination and degradation accounted for the increase in ERα protein expression. ERα is a key transcription factor in sustaining the growth of breast cancer cells. Upon AKTIP loss, ERα transcriptional activity was upregulated, accompanied with an enrichment in ERα-associated gene signatures in the transcriptome. The functional consequences of AKTIP loss appeared to be subtype-dependent as no significant change has been observed in the phenotypes and signaling profiles of ERα-negative breast cancer cells upon AKTIP depletion. Importantly, while AKTIP-depleted cells were resistant towards single treatment with ERα antagonists or JAK2 inhibitor, JAK2 inhibitor re-sensitized AKTIP-depleted cells towards ERα inhibition with fulvestrant.

Together, the present study revealed the mechanistic basis of AKTIP loss in the tumorigenesis of ERα-positive breast cancer, which represents potential treatment avenues for AKTIP-depleted breast cancer patients through the co-targeting of ERα and JAK2/STAT3 signaling. In addition, AKTIP may serve as a novel biomarker for the stratification and prognostication of breast cancer patients.