RESUMEN
Here, we show that HEMATOLOGICAL AND NEUROLOGICAL EXPRESSED 1-LIKE (HN1L) is a targetable breast cancer stem cell (BCSC) gene that is altered in 25% of whole breast cancer and significantly correlated with shorter overall or relapse-free survival in triple-negative breast cancer (TNBC) patients. HN1L silencing reduced the population of BCSCs, inhibited tumor initiation, resensitized chemoresistant tumors to docetaxel, and hindered cancer progression in multiple TNBC cell line-derived xenografts. Additionally, gene signatures associated with HN1L correlated with shorter disease-free survival of TNBC patients. We defined HN1L as a BCSC transcription regulator for genes involved in the LEPR-STAT3 signaling axis as HN1L binds to a putative consensus upstream sequence of STAT3, LEPTIN RECEPTOR, and MIR-150. Our data reveal that BCSCs in TNBC depend on the transcription regulator HN1L for the sustained activation of the LEPR-STAT3 pathway, which makes it a potentially important target for both prognosis and BCSC therapy.
Asunto(s)
Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Receptores de Leptina/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones SCID , MicroARNs/genética , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/patología , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Receptores de Leptina/genética , Elementos de Respuesta , Factor de Transcripción STAT3/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC. METHODS: Representative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44(+) and CD24(-/low), or Aldefluor(+)) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro. RESULTS: Although there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone. CONCLUSIONS: Overall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment.
Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cetuximab/administración & dosificación , Epotilonas/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Currently, many breast cancer patients with localized breast cancer undergo breast-conserving therapy, consisting of local excision followed by radiation therapy. Following radiation therapy, breast cancer cells are noted to undergo induction of autophagy, development of radioresistance, and enrichment of breast cancer stem cell subpopulations. It is hypothesized that inhibition of the cytoprotective autophagy that arises following radiation therapy increases radiosensitivity and confers longer relapse-free survival by eliminating tumor-initiating breast cancer stem cells. Therefore, we reviewed the controversial role of autophagy in breast cancer tumorigenesis and progression, autophagy induction by radiotherapy, and utilization of autophagy inhibitors to increase radiosensitivity of breast cancer and to target radioresistant breast cancer stem cells.
