Targeting insulin-like growth factor - I receptor in breast cancer
Year: 2011
Type: dissertation
Abstract: Insulin-like growth factor-I receptor (IGF-IR) is integral to cancer cell proliferation, survival, migration, and invasion, and resistance to anti-cancer therapies in many human malignancies including breast cancer. Within the last few years several drugs targeting IGF-IR have entered clinical trials and are showing promising early results. One of the integral goals of my thesis is to identify patients who are most likely to benefit from therapy. The Lee Laboratory previously reported an IGF gene expression signature, based upon genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. Confirming that this signature can measure IGF activity, I report here that the signature is reversed in three different cancer models (cell lines or xenografts) treated with three different anti-IGF-IR therapies. The Lee laboratory originally reported that the IGF signature was present in triple-negative human breast cancers (TNBC), and I found here that the signature is similarly present in TNBC cell lines. Supporting a role for IGF-IR signaling in this subtype of breast cancer, I found that TNBC cell lines were especially sensitive to an IGF-IR tyrosine kinase inhibitor (BMS-754807), and that sensitivity was significantly correlated to expression of the IGF gene signature. Consistent with this, comparative gene expression analysis among the most resistant and sensitive cell lines identified 114 differentially expressed genes which identified TNBC as being sensitive. To examine this association further we determined levels and activity of the IGF-IR in several recently developed primary human TNBC tumorgraft models. I found high activity in many models, and chose the TNBC model MC1, which had the highest levels of both IGF signature score and IGF-IR expression and activity, for testing an anti-IGF-IR tyrosine kinase inhibitor (BMS-754807) in vivo. MC1 tumorgrafts treated with BMS-754807 as a single agent showed growth inhibition, and in combination with chemotherapy tumor regression occurred until no tumor was palpable. This regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. These data provide a clear biological rationale to test anti-IGF-IR therapy in combination with chemotherapy in patients with TNBC. While IGF-IR activity is elevated in TNBC, in vitro cell culture evidence suggests an interaction between IGF-IR and ErbB2 (otherwise known as HER2). To examine crosstalk between IGF-IR and ErbB2 in mammary tumorigenesis in vivo, I used two models of mouse mammary tumorigenesis, MMTV-CD8-IGF-IR (a constitutively active IGF-IR) and MMTV-ErbB2. Bi-transgenic (bigenic) mice expressing both CD8-IGF-IR and ErbB2 developed mammary tumors significantly faster than mice expressing either transgene alone. Histological analysis showed that ErbB2 tumors were predominantly adenocarcinomas, CD8-IGF-IR tumors were mixed adenosquamous carcinomas, and interestingly, bigenic tumors showed a phenotype resembling both oncogenes. All tumor types contained CK8-positive luminal epithelial cells. Interestingly, markers of myoepithelial (CK14) and progenitor (CK6) cells were only detected in mammary tumors arising from MMTV-CD8-IGF-IR mice and bigenic mice. This data is consistent with the notion that expression of IGF-IR in the mammary gland of transgenic mice may results in expansion myoepithelial cells expressing CK14 and progenitor cells expressing CK6 thus resulting in a mixed lineage differentiation in the tumor. We hypothesized that the difference in tumor histology may relate to the transformation of different progenitor cell types by IGF-IR and ErbB2. To investigate this, we have developed a mouse model system using avian RCAS retrovirus as vehicle to deliver CD8-IGF-IR or ErbB2 into mammary glands of transgenic mice expressing the avian receptor TVA under the control of a MMTV promoter. This allows retroviral infection of specific mammary cell types in vivo. Mammary intraductal injection of RCAS-CD8-IGF-IR into MMTV-TVA transgenic mice resulted in expansion of CK14 cells and disruption of normal mammary gland architecture. We are currently investigating the differences between CD8-IGF-IR and ErbB2-induced mammary tumorigenesis using this novel viral transduction system. In summary, I have shown that the IGF-IR pathway is active in TNBC and that inhibition of IGF-IR using a small molecule tyrosine kinase inhibitor in combination with chemotherapy results in tumor regression. In addition, I have found that IGF-IR interact with ErbB2 to promote mammary cancer in vivo. These two studies provide a rationale for clinical studies of anti-IGF-IR therapy in TNBC and ErbB2-positive breast cancer. Future studies will examine tissue from patients treated with these inhibitors to identify biomarkers that predict response to therapy. It is anticipated that successful use of anti-IGF-IR therapy will improve breast cancer outcome.
Source: RWTH Publications (RWTH Aachen)
Authors: Beate C. Litzenburger, Bernhard Lüscher
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1013575510