Pre-clinical validation of early molecular markers of sensitivity to aromatase inhibitors in a mouse model of post-menopausal hormone-sensitive breast cancer

• Published in: Breast cancer research and treatment Vol. 109; no. 3; pp. 463 - 470
• Main Authors: Urruticoechea, Ander, Aguilar, Helena, Solé, Xavier, Capellà, Gabriel, Martin, Lesley-Ann, Dowsett, Mitch, Germà-Lluch, Josep Ramon
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-06-2008; Springer; Springer Nature B.V
• Subjects: Animals; Aromatase Inhibitors - pharmacology; Biological and medical sciences; Biomarkers, Tumor - analysis; Biopsy, Needle; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer research; Cancer therapies; Cellular biology; Cyclin D; Cyclins - analysis; Disease Models, Animal; Drug therapy; Estrogens; Female; Gene Expression Regulation, Neoplastic - drug effects; Gynecology. Andrology. Obstetrics; Ki-67 Antigen - analysis; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Nitriles - pharmacology; Oncology; Peptides - analysis; Postmenopause; Preclinical Study; Receptors, Estrogen - analysis; Rodents; Trefoil Factor-1; Triazoles - pharmacology; Tumors; Biomarkers; Animal model; Breast cancer; Endocrine treatment; Aromatase inhibitors; Oestrogen receptor; Estrogen receptor; Breast disease; Endocrine gland; Genetic marker; Menopause; Biological marker; Molecular marker; Hormone; Validation; Aromatase inhibitor; Rodentia; Malignant tumor; Mammary gland diseases; Vertebrata; Sensitivity; Mammalia; Treatment; Mouse; Early; Endocrinology; Cancer; Hormonal receptor
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-007-9676-7

Introduction
Changes in breast cancer cell biology following hormonal treatment have been claimed as promising predictor markers of clinical benefit even outperforming clinical response. From previous work we selected 10 genes showing both a well known regulation by oestrogen and a high level of early transcriptional regulation following therapy with aromatase inhibitors. Here we use an animal breast cancer model to explore the feasibility of the determination of their expression in minimally invasive samples and to further assess the magnitude of their regulation by letrozole.
Animal and methods
Aromatase inhibitor sensitive breast cancer tumours were grown in athymic mice under supplement with androstenedione. Following initial tumour growth animals were assigned to a control group or to receive letrozole at two different dosages. Fine needle aspirates were obtained at the moment of treatment assignation and one week later. Expression of the following genes at both time points was determined: Ki-67, Cyclin D1, pS2, Trefoil Factor 3, PDZ domain containing 1, Ubiquitin-conjugating enzyme E2C, Stanniocalcin 2, Topoisomerase 2 alfa, MAN1A1 and FAS.
Results
Fine needles aspirates were found to be a feasible and reproducible technique for RNA extraction. Trefoil Factor 3, pS2, Cyclin D1 and Stanniocalcin 2 were significantly downregulated by letrozole. Among them pS2 appears to be most sensitive to aromatase inhibitor treatment even differentiating sub-optimal from optimal letrozole dosage.
Discussion
We present pre-clinical evidence to justify the exploration in clinical trials of pS2, Trefoil factor 3, Cyclin D1 and Stanniocalcin as dynamic markers of oestrogen-driven pathway activation.