TIG1 Promotes the Development and Progression of Inflammatory Breast Cancer through Activation of Axl Kinase

Abstract

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer, but the basis for its aggressive properties are not fully understood. In this study, we report that high tumoral expression of TIG1 (RARRES1), a functionally undefined membrane protein, confers shorter survival in IBC patients. TIG1 depletion decreased IBC cell proliferation, migration and invasion in vitro and inhibited tumor growth of IBC cells in vivo. We identified the receptor tyrosine kinase Axl as a TIG1 binding protein. TIG1 interaction stablilized Axl by inhibiting its proteasome-dependent degradation. TIG1-depleted IBC cells exhibited reduced Axl expression, inactivation of NF-κB and downregulation of MMP-9, indicating that TIG1 regulates invasion of IBC cells by supporting the Axl signaling pathway in IBC cells. Consistent with these results, treatment of IBC cells with the Axl inhibitor SGI-7079 decreased their malignant properties in vitro. Lastly, TIG1 expression correlated positively with Axl expression in primary human IBC specimens. Our findings establish that TIG1 positively modifies the malignant properties of IBC by supporting Axl function, advancing understanding of its development and rationalizing TIG1 and Axl as promising therapeutic targets in IBC treatment.

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

“…Anti-apoptotic signaling in IBC cells has been studied in the past, most prominently in the context of chemotherapeutic resistance. 39,40 A more recent example is the receptor tyrosine kinase Axl, which has recently been shown to have a significant role in the malignant behavior of IBC cells 16 and has been previously revealed to block the induction of apoptosis through Akt and Bcl-xL. 41 However, our study is the first (to our knowledge) to directly address the molecular mechanisms that allow IBC cell survival in the context of ECM detachment.…”

“…[11][12][13][14][15] More recently, evidence implicating the membrane protein TIG1 and the receptor tyrosine kinase Axl in the oncogenic behavior of IBC cells has been uncovered. 16 However, despite these advances, knowledge of the biological mechanisms underlying IBC pathogenesis remains fairly rudimentary, and additional research dedicated to understanding the unique molecular pathways involved in IBC progression remains essential.…”

Breast cancer subtype dictates DNA methylation and ALDH1A3-mediated expression of tumor suppressor RARRES1

“…These are in contrast to a functional study in the rare inflammatory subtype of breast cancer (representing less than 5% of all breast cancers), where RARRES1 was oncogenic [16]. Furthermore, given these prior reports of both tumor suppressing and oncogenic effects of RARRES1, we considered if RARRES1 expression in a breast cancer subtype influences its function.…”

“…Our own work identified the cancer stem cell marker and retinoic-acid (RA) producing enzyme, aldehyde dehydrogenase 1A3 (ALDH1A3), as promoting or suppressing tumor growth in a context-dependent manner in TNBC [15]. The RA receptor responder protein 1 (RARRES1) has also been identified as either suppressing or promoting tumor growth, depending on the study [16,17]. …”

Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival

“…Among MPA-and ETO-regulated genes, H19 imprinted maternally expressed transcript, noncoding RNA (H19), TMEM119, RARRES1, and chemokine (C-C motif) ligand 2 (CCL2) mediate differentiation, proliferation, and migration of VSMCs (15)(16)(17)(18) and were thus chosen for quantitative RT-PCR (qRT-PCR) confirmation. In parallel with the microarray results (Tables S1 and S2), MPA or ETO up-regulated H19 mRNA and TMEM119 mRNA, and down-regulated RARRES1 mRNA and CCL2 mRNA levels (Fig.…”