Absence of the K303R estrogen receptor α mutation in breast cancer patients exhibiting different responses to aromatase inhibitor anastrozole neoadjuvant treatment

Ghimenti,Chiara; Mello-Grand,Maurizia; Regolo,Lea; Zambelli,Alberto; Chiorino,Giovanna

doi:10.3892/etm.2010.151

Absence of the K303R estrogen receptor α mutation in breast cancer patients exhibiting different responses to aromatase inhibitor anastrozole neoadjuvant treatment

Authors:
- Chiara Ghimenti
- Maurizia Mello-Grand
- Lea Regolo
- Alberto Zambelli
- Giovanna Chiorino
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Affiliations: Cancer Genomics Laboratory, Fondazione ‘Edo ed Elvo Tempia Valenta’, Via Malta 3, I-13900 Biella, Italy, Cancer Genomics Laboratory, Fondazione ‘Edo ed Elvo Tempia Valenta’, I-13900 Biella, Italy, Unit of Senology, IRCCS Fondazione ‘Salvatore Maugeri’, Pavia, Italy, Unit of Medical Oncology, IRCCS Fondazione ‘Salvatore Maugeri’, Pavia, Italy
Published online on: September 17, 2010 https://doi.org/10.3892/etm.2010.151
Pages: 939-942

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Abstract

Aromatase inhibitors, such as anastrozole, are established in the treatment of hormone-dependent breast cancer. However, approximately 20% of patients treated with anastrozole do not respond, and it remains impossible to accurately predict sensitivity. Thus, novel markers to predict response are required. The K303R estrogen receptor (ER)α mutation confers resistance to tamoxifen treatment. Moreover, K303R-expressing MCF-7 cells, transfected with an aromatase expression vector and stimulated with androstenedione (an aromatase substrate), were found to be resistant to the inhibitory effect of anastrozole. The aim of this study was to verify whether the presence of the K303R ERα mutation is associated with response to 3-month neoadjuvant treatment with anastrozole (Arimidex) in a cohort of post-menopausal breast cancer patients. Of 37 patients with ER+ tumors, 19 showed a clinical response to anastrozole and 18 were resistant. Biopsies were obtained from tumors responding to the therapy or from non-responding tumors. None carried the K303R ERα mutation. To our knowledge, this is the first study to search for K303R ERα mutations in tumors clinically responsive or resistant to an aromatase inhibitor. Lack of the mutation leads us to believe that this mutation has in vivo biological significance in only a subset of breast cancers.

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1.	Chalbos D, Vignon F, Keydar I and Rochefort H: Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D). J Clin Endocrinol Metab. 55:276–283. 1982. View Article : Google Scholar : PubMed/NCBI
2.	Russo J and Russo IH: The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 102:89–96. 2006. View Article : Google Scholar : PubMed/NCBI
3.	Beatson G: On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 147:101–107. 1986.
4.	Smith IE and Dowsett M: Aromatase inhibitors in breast cancer. N Engl J Med. 348:2431–2442. 2003. View Article : Google Scholar : PubMed/NCBI
5.	Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med. 339:1609–1618. 1998. View Article : Google Scholar : PubMed/NCBI
6.	Allred DC, Mohsin SK and Fuqua SA: Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer. 8:47–61. 2001. View Article : Google Scholar : PubMed/NCBI
7.	Elledge RM and Fuqua SAW: Estrogen and progesterone receptors. Diseases of the Breast. Harris JR, Lippman ME, Morrow M, et al: Lippincott, Williams & Wilkins; Philadelphia: pp. 471–488. 2000
8.	Hopp TA, Weiss HL, Parra IS, Cui Y, Osborne CK and Fuqua SA: Low levels of estrogen receptor β protein predict resistance to tamoxifen therapy in breast cancer. Clin Cancer Res. 10:7490–7499. 2004.
9.	Pike MC, Spicer DV, Dahmoush L and Press MF: Estrogens, progestins, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev. 15:17–35. 1993.PubMed/NCBI
10.	McGuire WL, Chamness GC and Fuqua SA: Estrogen receptor variants in clinical breast cancer. Mol Endocrinol. 5:1571–1577. 1991. View Article : Google Scholar : PubMed/NCBI
11.	Herynk MH, Parra I, Cui Y, Beyer A, Wu MF, Hilsenbeck SG and Fuqua SA: Association between the estrogen receptor α A908G mutation and outcomes in invasive breast cancer. Clin Cancer Res. 13:3235–3243. 2007.
12.	Fuqua SA, Wiltschke C, Zhang QX, Borg A, Castles CG, Friedrichs WE, Hopp T, Hilsenbeck S, Mohsin S, O'Connell P and Allred DC: A hypersensitive estrogen receptor-α mutation in premalignant breast lesions. Cancer Res. 60:4026–4029. 2000.
13.	Tebbit CL, Bentley RC, Olson JA Jr and Marks JR: Estrogen receptor α (ESR1) mutant A908G is not a common feature in benign and malignant proliferations of the breast. Genes Chromosomes Cancer. 40:51–54. 2004.
14.	Tokunaga E, Kimura Y and Maehara Y: No hypersensitive estrogen receptor-α mutation (K303R) in Japanese breast carcinomas. Breast Cancer Res Treat. 84:289–292. 2004.
15.	Davies MP, O'Neill PA, Innes H and Sibson DR: Hypersensitive K303R oestrogen receptor-α variant not found in invasive carcinomas. Breast Cancer Res. 7:R113–R118. 2005.
16.	Zhang Z, Yamashita H, Toyama T, Omoto Y, Sugiura H, Hara Y, Haruki N, Kobayashi S and Iwase H: Estrogen receptor α mutation (A-to-G transition at nucleotide 908) is not found in different types of breast lesions from Japanese women. Breast Cancer. 10:70–73. 2003.
17.	Conway K, Parrish E, Edmiston SN, Tolbert D, Tse CK, Geradts J, Livasy CA, Singh H, Newman B and Millikan RC: The estrogen receptor-α A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study. Breast Cancer Res. 7:R871–R880. 2005.
18.	Cui Y, Zhang M, Pestell R, Curran EM, Welshons WV and Fuqua SA: Phosphorylation of estrogen receptor α blocks its acetylation and regulates estrogen sensitivity. Cancer Res. 64:9199–9208. 2004.
19.	Giordano C, Cui Y, Barone I, Ando S, Mancini MA, Berno V and Fuqua SA: Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor alpha and its phosphorylation at serine 305. Breast Cancer Res Treat. 119:71–85. 2010. View Article : Google Scholar : PubMed/NCBI
20.	Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, van Glabbeke M, van Oosterom AT, Christian MC and Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 92:205–216. 2000. View Article : Google Scholar
21.	Barone I, Cui Y, Herynk MH, Corona-Rodriguez A, Giordano C, Selever J, Beyer A, Andò S and Fuqua SA: Expression of the K303R estrogen receptor-α breast cancer mutation induces resistance to an aromatase inhibitor via addiction to the PI3K/Akt kinase pathway. Cancer Res. 69:4724–4732. 2009.
22.	Conway K, Parrish E, Edmiston SN, Tolbert D and Tse CK: Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation. Breast Cancer Res. 9:R362007. View Article : Google Scholar : PubMed/NCBI
23.	Li CI, Malone KE, Porter PL, Weiss NS and Tang MT: Reproductive and anthropometric factors in relation to the risk of lobular and ductal breast carcinoma among women 65–79 years of age. Int J Cancer. 107:647–651. 2003.PubMed/NCBI