β1 Integrin is essential for fascin‐mediated breast cancer stem cell function and disease progression

Abstract

Breast cancer remains the second cause of tumor‐related mortality in women worldwide mainly due to chemoresistance and metastasis. The chemoresistance and metastasis are attributed to a rare subpopulation with enriched stem‐like characteristics, thus called Cancer Stem Cells (CSCs). We have previously reported aberrant expression of the actin‐bundling protein (fascin) in breast cancer cells, which enhances their chemoresistance, metastasis and enriches CSC population. The intracellular mechanisms that link fascin with its downstream effectors are not fully elucidated. Here, loss and gain of function approaches in two different breast cancer models were used to understand how fascin promotes disease progression. Importantly, findings were aligned with expression data from actual breast cancer patients. Expression profiling of a large breast cancer dataset (TCGA, 530 patients) showed statistically significant correlation between fascin expression and a key adherence molecule, β1 integrin (ITGB1). In vitro manipulation of fascin expression in breast cancer cells exhibited its direct effect on ITGB1 expression. Fascin‐mediated regulation of ITGB1 was critical for several breast cancer cell functions including adhesion to different extracellular matrix, self‐renewability and chemoresistance. Importantly, there was a significant relationship between fascin and ITGB1 co‐expression and short disease‐free as well as overall survival in chemo‐treated breast cancer patients. This novel role of fascin effect on ITGB1 expression and its outcome on cell self‐renewability and chemoresistance strongly encourages for dual targeting of fascin‐ITGB1 axis as a therapeutic approach to halt breast cancer progression and eradicate it from the root.

The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1

“…The contribution of FSCN1 to tumor and metastasis progression has been experimentally addressed in various carcinoma cell lines and mouse models and has generally been attributed to its function in driving tumor cell motility and invasion . Additionally, FSCN1 has been implicated in oncogenesis, chemoresistance, anoikis resistance, and cancer cell stemness via multiple signaling pathways . A recent report provided evidence that FSCN1 promotes metabolic stress resistance and thereby controls metastatic colonization in lung cancer .…”

Fascin Activates β-Catenin Signaling and Promotes Breast Cancer Stem Cell Function Mainly Through Focal Adhesion Kinase (FAK): Relation With Disease Progression

“…Our previous work on breast cancer cells revealed a critical role for fascin in conferring chemoresistance via activation of FAK (5), a molecular adaptor that binds β1 integrin (19) and fascin (20) in breast cancer cells. In a subsequent study, we demonstrated that fascin expression in breast cancer cells induces β1 integrin to sustain FAK activation (7), which is also required for nuclear translocation of β-catenin and transcriptional activation of the β-catenin target genes (9). Whether FAK activates β-catenin signaling pathway in breast cancer and whether it is fascin-dependent have not been investigated.…”

“…The MDA-MB-231 (HTB-26) and T-47D (HTB-133) breast cancer cell lines were purchased from ATCC (Manassas, VA, USA) and were maintained in culture as previously described (7). Cells were routinely screened for mycoplasma using a polymerase chain reaction (PCR)-based kit (iNtRON, Sangdaewon-Dong, Jungwon-Gu, Seongnam-Si, Gyeonggi-do, Korea).…”

“…Fascin stable knockdown (fascin − ) and control (fascin + ) were established in the naturally fascin-positive MDA-MB-231 cells using fascin and scrambled ShRNA, respectively, as previously described (4). Fascin was also ectopically expressed in the naturally fascin-negative T-47D cells or rescued in the fascinknockdown (fascin − ) MDA-MB-231 cells using fascin ORF (FORF) or control ORF as previously described (7). The knockdown and expression of fascin were routinely confirmed using Western blot.…”

“…Fascin is an actin-bundling protein that is induced in many neoplasms including breast cancer (3), and we have previously showed that it enhances metastasis (4) and confers resistance to chemotherapy (5) through direct regulation of CSC population (6). Most recently, we have demonstrated that fascin enhances β1 integrin expression, a critical step for activation of the focal adhesion kinase (FAK) and subsequent regulation of CSC function (7). Other studies showed that FAK expression, which is often enhanced in breast cancer (8), is required for nuclear translocation of β-catenin and transcriptional activation of the β-catenin target genes (9).…”