Current medical treatment strategies for breast cancer in clinical practice include endocrine therapy, anti-HER-2 therapy and chemotherapy [
1‐
3]. Endocrine therapy is used for patients whose tumors express estrogen receptor (ER). Letrozole is a new generation of highly selective aromatase inhibitors (AIs) which is used for endocrine therapy. Aromatase is involved in the conversion of testosterone to estrogen and is the rate-limiting enzyme. Because AIs could inhibit the production of estrogen, they are especially used as the first-line drugs for post-menopause ER positive metastatic breast cancer, and adjunctive therapy drugs for early breast cancer [
4‐
6]. Chemotherapy is the best therapeutic approach for patients who develop resistance to anti-HER-2 therapy and endocrine therapy. Cisplatin is a common chemotherapy drug usually used to treat breast cancer. The anti-cancer activity of cisplatin is involved in its binding with DNA. The formation of DNA–cisplatin complex blocks DNA replication or inhibits transcription [
7,
8]. However, breast cancer cells often develop resistance to cisplatin in clinic. At present, the actual mechanisms of cisplatin resistance are not fully understood. The currently known mechanisms comprise increased DNA repair, cytosolic inactivation and altered cellular accumulation of drug [
9‐
11]. The enhanced DNA repair ability has been demonstrated to be the key factor to result in cisplatin resistance. The increased ability of base excision repair (BER), nucleotide excision repair (NER) and mismatch repair in DNA repair pathway is considered to be involved in cisplatin resistance, and NER might be one of the most important mechanisms [
9,
12].
FEN1 is a structure-specific endonuclease. It has flap endonuclease, gap-endonuclease activities and 5′-exonuclease [
13,
14]. These properties make it possible for FEN1 to take part in multiple pathways of DNA metabolisms, such as maintenance of telomere, stalled replication fork rescue, apoptotic DNA fragmentation and Okazaki fragment maturation [
15,
16]. FEN1 is overexpressed in multiple cancers, including metastatic prostate cancer [
17], pancreatic cancer [
18], neurocytoma [
19] and breast cancer [
20]. In breast cancer, FEN1 overexpression is considered as a potential therapy target and biomarker to monitor cancer progression [
20,
21], and involved in resistance to a lot of chemotherapeutic drugs such as cisplatin [
22‐
24]. Evidence suggests that FEN1 expression can be regulated by estrogen. Estrogen regulates FEN1 expression in uterine tissue whose biology is closely related to breast tissue [
25]. FEN1 expression is up-regulated 2.63-fold by estrogen in MCF-7 breast cancer cells, though the exact mechanism is not clear [
26]. The 5′ flanking region of FEN1 includes two CpG islands which regulate FEN1 promoter activity, and hypomethylation of FEN1 promotor up-regulates FEN1 expression in breast cancer [
20]. However, the hypomethylation mechanism can not fully explain estrogen-induced FEN1 overexpression. Estrogen-induced genes expression is generally controlled by transcriptional factor Elk-1, whose phosphorylation activity is regulated by MAPK/ERK [
27,
28]. Bioinformatics analysis shows the presence of four potential Elk-1 binding sites and the absence of ER-binding sites in FEN1 promoter region. Our previous study has demonstrated that increased MAPK/ERK phosphorylation contributes to FEN1 overexpression which could be induced by cisplatin in breast cancer cells [
24]. It is indicated that ERK/Elk-1 signaling may be involved in estrogen-induced FEN1 up-regulation in breast cancer cells.
In this study, the effects of letrozole on FEN1 expression and cisplatin sensitivity in breast cancer cells overexpressing aromatase were explored. We found that letrozole improved cisplatin sensitivity of MCF-7aro cells, a kind of aromatase overexpressing breast cancer cells. The sensitizing effect of letrozole to cisplatin was involved in FEN1 down-regulation through the inhibition of the ERK/Elk-1 signaling.