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Georgia Journal of Science

Article Title

THE ROLE OF RBP-JK IN LEPTIN-INDUCTION OF BREAST CANCER PROGRESSION AND CHEMORESISTANCE

Abstract

In cancer tissues leptin and its receptor, ObR, are significantly overexpressed, where Notch signaling is altered. In obese individuals, leptin levels are abnormally high. Accumulated data from the Gonzalez lab suggests that leptin induces the expression of Notch, its nuclear partner RBP-JK, and cancer stem cell expansion. These leptin-induced effects are related to higher cancer incidence and aggressiveness, chemoresistance, and poor prognosis in obese patients. RBP-JK is a tumor suppressor and key regulator of leptin-induced Notch signals that increase cancer cell proliferation. RBP-JK was reported to be down regulated in solid tumors and linked to more aggressive cancer. It is hypothesized that loss of RBP-JK would induce constitutive activation of Notch target genes and cell proliferation independent of leptin and Notch crosstalk signaling. The parental murine breast cancer cell line EO771 [estrogen receptor (ER+), and Progesterone receptor (PgR-) and Her2-) and its derivative cell line Tamoxifen-resistant (TAM-EO771, unresponsive to estrogen) were genetically modified using CRISPR/Cas9 technology to knock out RBP-JK gene. Cells were treated with leptin and a chemotherapeutic [Paclitaxel (TAX)] and their effects on cell cycle, proliferation and survival were determined using Cellometer technology and MTT assay, respectively. Results show that leptin is a proliferative factor for EO771 cancer cells. However, leptin induced greater proliferation effects in RBP-JK-/- cells. RBP-JK -/- cells displayed higher TAX resistance capability in comparison to RBP-JK+ cells. Our results suggest that loss of RBP-JK allows leptin-induction of Notch-independent activation by alternate mechanisms. Additionally, leptin induces more Notch3 and Notch4 in RBP-JK-/- cells that can affect chemoresistance and cell proliferation. These data open the possibility that targeting leptin signaling and RBP-JK gene expression could be a new way to treat breast cancer progression and chemoresistance.

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