Abstract
Triple Negative Breast Cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by the absence of hormone receptors usually targeted by hormone therapies like Tamoxifen. Because therapy success and survival rates for TNBC lag far behind other breast cancer subtypes, there is significant interest in developing novel anti-TNBC agents that can target TNBC specifically, with minimal effects on non-malignant tissue. To this aim, our study describes the anti-TNBC effect of strictinin, an ellagitanin previously isolated from Myrothamnus flabellifolius. Using various in silico and molecular techniques, we characterized the mechanism of action of strictinin in TNBC. Our results suggest strictinin interacts strongly with Receptor Tyrosine Kinase Orphan like 1 (ROR1). ROR1 is an oncofetal receptor highly expressed during development but not in normal adult tissue. It is highly expressed in several human malignancies however, owing to its numerous pro-tumor functions. Via its interaction and inhibition of ROR1, strictinin reduced AKT phosphorylation on ser-473, inhibiting downstream phosphorylation and inhibition of GSK3β. The reduction in AKT phosphorylation also correlated with decreased cell survival and activation of the caspase-mediated intrinsic apoptotic cascade. Strictinin treatment also repressed cell migration and invasion in a beta-catenin independent manner, presumably via the reactivated GSK3ß’s repressing effect on microtubule polymerization and focal adhesion turnover. This could be of potential therapeutic interest considering heightened interest in ROR1 and other receptor tyrosine kinases as targets for development of anti-cancer agents. Further studies are needed to validate these findings in other ROR1-expressing malignancies but also in more systemic models of TNBC. Our findings do however underline the potential of strictinin and other ROR1-targeting agents as therapeutic tools to reduce TNBC proliferation, survival and motility.
Highlights
One in eight women are diagnosed with breast cancer each year
Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer characterized by malignant cells void of hormone (Progesterone and Estrogen) receptors and Human Epidermal Growth Factor Receptor 2 (HER-2) [2]
There has been an increased effort to look for novel agents that can treat triple negative breast cancer or complement existing drugs, with minimal effects on nonmalignant cells
Summary
One in eight women are diagnosed with breast cancer each year. Of these new cases, 15–20% are Triple Negative [1]. Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer characterized by malignant cells void of hormone (Progesterone and Estrogen) receptors and Human Epidermal Growth Factor Receptor 2 (HER-2) [2] The lack of these receptors, usually targeted by hormonal therapies like tamoxifen and fulvestrant, leads to an increased difficulty in treatment. Traditional chemotherapeutics and radiation used in breast cancer therapy are often highly toxic to both TNBC cells and healthy cells. This leads to many negative and unwanted side effects, often causing a decrease in therapy adherence in patients. There has been an increased effort to look for novel agents that can treat triple negative breast cancer or complement existing drugs, with minimal effects on nonmalignant cells
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