Jordan Han

Introduction: Breast cancer accounts for up to 23% of all cancer deaths in postmenopausal women¹. Estrogen-receptor positive breast cancers are still one of the most common types of breast cancer today, and are commonly treated by aromatase inhibitors or estrogen receptor inhibitors². Aromatase inhibitors remain one of the first lines of defense against ER-positive breast cancers, but treatment has been complicated by a concurrent rise in aromatase inhibitor resistance². In recent years there has been a push to try and overcome this resistance using the PI3K/AKT/mTOR and MAPK pathways, which have both been found to be implicated in aromatase inhibitor resistance². The mTOR complex additionally mediates IGF-1R receptor response and growth in breast cancer cells, meaning mutations in the IGF pathway may confer resistance to mTORC1 inhibitors and further aberrant signaling³. Because of the extensive crosstalk between the PI3K/AKT/mTOR pathway, IGF pathway, and estrogen signaling, this suggests that use of combination therapies to target these pathways may be needed to overcome aromatase inhibitor resistance³. Methods: 1) ER+ breast cancer cells were treated with an mTOR inhibitor and then treated with aromatase inhibitors and lysed, analyzed via immunoblot analysis⁴. 2) An anti-IGF-1R antibody, mTORC1 inhibitor, and letrozole were assessed in athymic mice with hormone-sensitive breast cancer tumor xenograft transfected with the aromatase gene³. 3) IGF-1R selective tyrosine kinase inhibitor, fulvestrant, and IGF-1 were added to MCF-7-E10 breast cancer cells and then harvested. Cells were lysed and subjected to Western blot analysis and RT-PCR⁵. Results: 1) Post-letrozole treated tumor cells showed lower IGF-1R levels than untreated, and decreased MAPK phosphorylation⁴. 2) Combined triple therapy using an aromatase inhibitor such as letrozole, combined with an anti-IGF-1R antibody and mTOR inhibitor have better antitumor effects in ER-positive human breast cancer, and may be able to treat aromatase inhibitor resistant cancer lines³. 3) IGF and ER signaling confer a net proliferative effect that can be suppressed by the addition of fulvestrant, suggesting IGF-1R inhibition may be an important addition to cancer therapy to further decrease PI3K/AKT/mTOR signalling⁵. Conclusion: Triple combination with an IGF-1R inhibitor, an aromatase/ER inhibitor, and an mTOR inhibitor has been proposed as an effective way to overcome multiple resistances in ER-positive breast cancer^3. This treatment leads to the lowest levels of IGF-1R, phosphorylated IGF-1R/IR, AKT, and MAPK³. Thus exploitation of the extensive cross-talk between these pathways may lead to better outcomes for the patient, including reduced tumor size and greater cytostatic effect.

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