IGF1R Inhibition in Mammary Epithelia Promotes Canonical Wnt Signaling and Wnt1-Driven Tumors

Abstract

Triple-negative breast cancers (TNBC) are an aggressive disease subtype which unlike other subtypes lack an effective targeted therapy. Inhibitors of the insullin-like growth factor receptor (IGF-1R) have been considered for use in treating TNBC. Here we provide genetic evidence that IGF-1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt-1 and mutant IGF-1R, a reduction in IGF-1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamal cell phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacological inhibition of the IGF-1R in vitro was sufficient to increase the tumorsphere-forming efficiency of MMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor vs the IR-B isoform, which in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors an attenuation of IGF-1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes, with potential implications for understanding TNBC pathobiology and treatment.

Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation

“…Accordingly, lack of Igf1 and Igf1r was reported to promote cell proliferation and/or to alter epithelial differentiation not only in the lung [25, 26, 28, 29, 31], but also in the prostate, thyroid gland, liver and nervous system[31, 44, 72, 73]. Furthermore, limited activity of Igf1r accelerates tumorigenesis and promotes more aggressive phenotypes in prostate and breast cancer in mice [72, 74]. Despite this hyperproliferative effect we did not see any hyperplasias in the airway epithelium of the Igf1r conditional mutants.…”

Discrimination of tumor from normal tissues in a mouse model of breast cancer using CARS spectroscopy combined with PC‐DFA methodology

“…MMTV‐Wnt‐1 mice have constitutive overexpression of the Wnt‐1 ligand under the MMTV promoter within the epithelial cells of the mammary gland. This overexpression of Wnt‐1 promotes oncogenes via the canonical Wnt pathway, thus leading to the spontaneous formation of massive mammary tumors typically characterized as basal‐like in their molecular subtype . Basal‐like tumors are considered to have the poorest prognostic outcome in breast cancer patients, in part due to their unresponsiveness to hormone therapy and lack of a targeted therapy, and because they are more prone to invade surrounding tissues and metastasize .…”

“…This overexpression of Wnt‐1 promotes oncogenes via the canonical Wnt pathway, thus leading to the spontaneous formation of massive mammary tumors typically characterized as basal‐like in their molecular subtype . Basal‐like tumors are considered to have the poorest prognostic outcome in breast cancer patients, in part due to their unresponsiveness to hormone therapy and lack of a targeted therapy, and because they are more prone to invade surrounding tissues and metastasize . Unfortunately, basal tumors also possess a high rate of recurrence following surgical clearance, believed to be in part from having an enriched cancer stem cell population and their ability to invade and metastasize .…”

Subventricular zone adult mouse neural stem cells and human glioblastoma stem cells require insulin receptor for self-renewal

“…In breast and colorectal cancers, IGF-1R promotes the proliferation of the progenitors within the tumor (Farabaugh et al, 2015;Rota et al, 2014). As shown in Table 2, there is a switch in the ratio of IGF-1R to IR-A in the GBM spheres compared to normal human neural stem cells.…”