Abstract
The triple-negative breast cancer (TNBC) subtype is enriched in cancer stem cells (CSCs) and clinically correlated with the highest rate of recurrence. Several studies implicate the RSK pathway as being pivotal for the growth and proliferation of CSCs, which are postulated to drive tumor relapse. We now address the potential for the newly developed RSK inhibitor LJI308 to target the CSC population and repress TNBC growth and dissemination. Overexpression of the Y-box binding protein-1 (YB-1) oncogene in human mammary epithelial cells (HMECs) drove TNBC tumor formation characterized by a multi-drug resistance phenotype, yet these cells were sensitive to LJI308 in addition to the classic RSK inhibitors BI-D1870 and luteolin. Notably, LJI308 specifically targeted transformed cells as it had little effect on the non-tumorigenic parental HMECs. Loss of cell growth, both in 2D and 3D culture, was attributed to LJI308-induced apoptosis. We discovered CD44+/CD49f+ TNBC cells to be less sensitive to chemotherapy compared to the isogenic CD44-/CD49f- cells. However, inhibition of RSK using LJI308, BI-D1870, or luteolin was sufficient to eradicate the CSC population. We conclude that targeting RSK using specific and potent inhibitors, such as LJI308, delivers the promise of inhibiting the growth of TNBC.
Highlights
Despite being identified as aggressive with high rates of relapse and poor survival over a decade ago, treatment and management of triple-negative breast cancer (TNBC) remains a significant clinical problem [1, 2]
Our group recently reported that induction of Y-box binding protein-1 (YB-1) could transform human mammary epithelial cells (HMECs) into carcinoma cells through a cancer stem cells (CSCs)-enriched intermediate (Fig. 1A), the phenotypes of which are summarized in Table 1 [10]
Cultures established following long-term YB-1 over-expression (HTRY-LT1 and HTRY-LT2) formed www.impactjournals.com/oncotarget tumors when transplanted into mice that were molecularly subtyped as TNBC [10]
Summary
Despite being identified as aggressive with high rates of relapse and poor survival over a decade ago, treatment and management of triple-negative breast cancer (TNBC) remains a significant clinical problem [1, 2]. Attacking these tumors with anthracycline-based chemotherapies does not improve outcomes [3]. Large screening efforts using small interfering RNAs identified RPS6KA3 (encoding RSK2) as being absolutely required to sustain the growth of estrogen-receptor negative breast cancer suggesting it may be a relevant target [6, 7]. We evaluated the potential of the new pan-RSK inhibitor LJI308 in inhibiting the growth and survival of TNBC
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