Mitochondrial transcription factor A contributes to cisplatin resistance in patients with estrogen receptor‑positive breast cancer

Gao,Wei; Wu,Mei‑Hong; Wang,Ning; Ying,Ming‑Zheng; Zhang,Ying‑Yi; Hua,Jing; Chuan,Liu; Wang,Ya‑Jie

doi:10.3892/mmr.2016.5881

Mitochondrial transcription factor A contributes to cisplatin resistance in patients with estrogen receptor‑positive breast cancer

Authors:
- Wei Gao
- Mei‑Hong Wu
- Ning Wang
- Ming‑Zheng Ying
- Ying‑Yi Zhang
- Jing Hua
- Liu Chuan
- Ya‑Jie Wang
View Affiliations

Affiliations: Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: October 25, 2016 https://doi.org/10.3892/mmr.2016.5881
Pages: 5304-5310

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies have reported that triple-negative breast cancer is more sensitive to cytotoxic treatment, compared with estrogen receptor (ER)‑positive cancer. However, the underlying molecular mechanisms remain to be fully elucidated. In the present study, we employed reverse transcription‑quantitative polymerase chain reaction, western blot and in vivo assays to investigate the underlying mechanisms. The sensitivities of cells to cisplatin were examined in ER-positive and ER‑negative breast cancer cells, and it was found that the ER‑negative cells were more sensitive to cisplatin, compared with the ER‑positive cells. In addition, it was found that mitochondrial transcription factor A (TFAM), which functions in mitochondrial DNA replication and repair, was expressed at a high level in ER‑positive cell lines and patient tissues, compared with ER‑negative cell lines and tissues. It was also found that the sensitivity to cisplatin was decreased when TFAM was knocked down in the breast cancer cells, and these effects were reversed when TFAM was reintroduced to the cells. Similar results were observed in xenograft tumors. The results of the present study provided evidence that resistance to cisplatin chemotherapy in ER‑positive breast cancer may be through TFAM and indicated that TFAM may be a target for chemoresistance in patients with breast cancer. These findings offer potential guidance for chemotherapy in patients with breast cancer.

View Figures

View References

1	DeSantis C, Ma J, Bryan L and Jemal A: Breast cancer statistics, 2013. CA Cancer J Clin. 64:52–62. 2014. View Article : Google Scholar : PubMed/NCBI
2	Kwok JM, Peck B, Monteiro LJ, Schwenen HD, Millour J, Coombes RC, Myatt SS and Lam EW: FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol Cancer Res. 8:24–34. 2010. View Article : Google Scholar : PubMed/NCBI
3	Zhang J, Wang Z, Hu X, Wang B, Wang L, Yang W, Liu Y, Liu G, Di G, Hu Z, et al: Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer. Int J Cancer. 136:204–211. 2015. View Article : Google Scholar : PubMed/NCBI
4	Siddik ZH: Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene. 22:7265–7279. 2003. View Article : Google Scholar : PubMed/NCBI
5	Yazlovitskaya EM and Persons DL: Inhibition of cisplatin-induced ATR activity and enhanced sensitivity to cisplatin. Anticancer Res. 23:2275–2279. 2003.PubMed/NCBI
6	Wei Q, Dong G, Yang T, Megyesi J, Price PM and Dong Z: Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 293:F1282–F1291. 2007. View Article : Google Scholar : PubMed/NCBI
7	Yoshida K, Ozaki T, Furuya K, Nakanishi M, Kikuchi H, Yamamoto H, Ono S, Koda T, Omura K and Nakagawara A: ATM-dependent nuclear accumulation of IKK-alpha plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin. Oncogene. 27:1183–1188. 2008. View Article : Google Scholar : PubMed/NCBI
8	Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA and Slamon DJ: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol. 16:2659–2671. 1998.PubMed/NCBI
9	Sui M, Zhang H and Fan W: The role of estrogen and estrogen receptors in chemoresistance. Curr Med Chem. 18:4674–4683. 2011. View Article : Google Scholar : PubMed/NCBI
10	Mattingly KA, Ivanova MM, Riggs KA, Wickramasinghe NS, Barch MJ and Klinge CM: Estradiol stimulates transcription of nuclear respiratory factor-1 and increases mitochondrial biogenesis. Mol Endocrinol. 22:609–622. 2008. View Article : Google Scholar : PubMed/NCBI
11	Cam H, Balciunaite E, Blais A, Spektor A, Scarpulla RC, Young R, Kluger Y and Dynlacht BD: A common set of gene regulatory networks links metabolism and growth inhibition. Mol Cell. 16:399–411. 2004. View Article : Google Scholar : PubMed/NCBI
12	Kang D, Kim SH and Hamasaki N: Mitochondrial transcription factor A (TFAM): Roles in maintenance of mtDNA and cellular functions. Mitochondrion. 7:39–44. 2007. View Article : Google Scholar : PubMed/NCBI
13	Hallberg BM and Larsson NG: TFAM forces mtDNA to make a U-turn. Nat Struct Mol Biol. 18:1179–1181. 2011. View Article : Google Scholar : PubMed/NCBI
14	Yang Z, Schumaker LM, Egorin MJ, Zuhowski EG, Guo Z and Cullen KJ: Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: Possible role in apoptosis. Clin Cancer Res. 12:5817–5825. 2006. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, Kladny J, Gorski B, Lubinski J and Narod SA: Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat. 115:359–363. 2009. View Article : Google Scholar : PubMed/NCBI
17	Hsieh CY, Santell RC, Haslam SZ and Helferich WG: Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 58:3833–3838. 1998.PubMed/NCBI
18	Ström A, Hartman J, Foster JS, Kietz S, Wimalasena J and Gustafsson JA: Estrogen receptor beta inhibits 17beta-estradiolstimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci USA. 101:1566–1571. 2004. View Article : Google Scholar : PubMed/NCBI
19	Ferguson AT, Lapidus RG, Baylin SB and Davidson NE: Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res. 55:2279–2283. 1995.PubMed/NCBI
20	Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C and Gerald WL: An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 25:3994–4008. 2006. View Article : Google Scholar : PubMed/NCBI
21	Li L and Yu AQ: The functional role of peroxiredoxin 3 in reactive oxygen species, apoptosis, and chemoresistance of cancer cells. J Cancer Res Clin Oncol. 141:2071–2077. 2015. View Article : Google Scholar : PubMed/NCBI
22	Hosoya N and Miyagawa K: Targeting DNA damage response in cancer therapy. Cancer Sci. 105:370–388. 2014. View Article : Google Scholar : PubMed/NCBI
23	Gonzalez-Angulo AM, Morales-Vasquez F and Hortobagyi GN: Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 608:1–22. 2007. View Article : Google Scholar : PubMed/NCBI
24	Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, et al: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 28:1145–1153. 2010. View Article : Google Scholar : PubMed/NCBI
25	Funato T, Kozawa K, Kaku M and Sasaki T: Modification of the sensitivity to cisplatin with c-myc over-expression or down-regulation in colon cancer cells. Anticancer Drugs. 12:829–834. 2001. View Article : Google Scholar : PubMed/NCBI
26	Fraser M, Bai T and Tsang BK: Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 122:534–546. 2008. View Article : Google Scholar : PubMed/NCBI
27	Bradford CR, Zhu S, Ogawa H, Ogawa T, Ubell M, Narayan A, Johnson G, Wolf GT, Fisher SG and Carey TE: P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines. Head Neck. 25:654–661. 2003. View Article : Google Scholar : PubMed/NCBI
28	Niedner H, Christen R, Lin X, Kondo A and Howell SB: Identification of genes that mediate sensitivity to cisplatin. Mol Pharmacol. 60:1153–1160. 2001.PubMed/NCBI
29	Funato T, Kozawa K, Kaku M and Sasaki T: Modification of the sensitivity to cisplatin with c-myc over-expression or down-regulation in colon cancer cells. Anticancer Drugs. 12:829–834. 2001. View Article : Google Scholar : PubMed/NCBI
30	Fraser M, Bai T and Tsang BK: Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int J Cancer. 122:534–546. 2008. View Article : Google Scholar : PubMed/NCBI
31	Olivero OA, Semino C, Kassim A, Lopez-Larraza DM and Poirier MC: Preferential binding of cisplatin to mitochondrial DNA of Chinese hamster ovary cells. Mutat Res. 346:221–230. 1995. View Article : Google Scholar : PubMed/NCBI
32	Kroemer G, Dallaporta B and Resche-Rigon M: The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 60:619–642. 1998. View Article : Google Scholar : PubMed/NCBI