Abstract
All-trans retinoic acid (ATRA), a pan-retinoic acid receptor (RAR) agonist, is, along with other retinoids, a promising therapeutic agent for the treatment of a variety of solid tumors. On the one hand, preclinical studies have shown promising anticancer effects of ATRA in breast cancer; on the other hand, resistances occurred. Autophagy is a cellular recycling process that allows the degradation of bulk cellular contents. Tumor cells may take advantage of autophagy to cope with stress caused by anticancer drugs. We therefore wondered if autophagy is activated by ATRA in mammary tumor cells and if modulation of autophagy might be a potential novel treatment strategy. Indeed, ATRA induces autophagic flux in ATRA-sensitive but not in ATRA-resistant human breast cancer cells. Moreover, using different RAR agonists as well as RARα-knockdown breast cancer cells, we demonstrate that autophagy is dependent on RARα activation. Interestingly, inhibition of autophagy in breast cancer cells by either genetic or pharmacological approaches resulted in significantly increased apoptosis under ATRA treatment and attenuated epithelial differentiation. In summary, our findings demonstrate that ATRA-induced autophagy is mediated by RARα in breast cancer cells. Furthermore, inhibition of autophagy results in enhanced apoptosis. This points to a potential novel treatment strategy for a selected group of breast cancer patients where ATRA and autophagy inhibitors are applied simultaneously.
Highlights
All-trans retinoic acid (ATRA), the active metabolite of vitamin A, exerts diverse functions in almost every cell and organ system
ATRA initiates a dose- and time-dependent autophagic response associated with epithelial differentiation in SKBR3 cells
To determine whether ATRA modulates autophagy in breast cancer cells, we first measured steadystate levels of the autophagy marker LC3B-II in the two luminal, human epidermal growth factor receptor-2 (HER2)-positive ER-negative breast cancer cell lines, SKBR3 (HER2/RARα coamplification) and MDA-MB453 (HER2 amplification), upon challenge with different concentrations of ATRA during different time periods. We chose these two cell lines as SKBR3 are sensitive to and MDA-MB453 cells are resistant to ATRA.[20]
Summary
All-trans retinoic acid (ATRA), the active metabolite of vitamin A, exerts diverse functions in almost every cell and organ system. ER-positive breast cancer patients are eligible for hormonal therapies, whereas HER2 oncogenic activity can be blocked using targeted therapies.[16] Approximately 15–20% of breast carcinomas overexpress HER2, which is associated with poor prognosis.[17] Owing to the development of resistance to current HER2-targeted treatments such as trastuzumab and lapatinib alternative therapeutic strategies are required.[18,19] ATRA was recently shown to exert strong antitumor activity in cell lines representing a subgroup of HER2-positive breast tumors characterized by coamplification of the ERBB2 and RARα genes.[20] This antitumor activity is remarkably stimulated by simultaneous HER2 inhibition with lapatinib. Autophagy is induced upon ATRA treatment of the APL-derived cell line NB49–11 and retinoids have clinical relevance in breast cancer. We evaluated whether autophagy modulation represents a potential therapeutic strategy for potentiating ATRA cytotoxicity in breast cancer cells
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