Abstract
BackgroundThe Oncotype DX 21-gene Recurrence Score is predictive of adjuvant chemotherapy benefit for women with early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. In premenopausal women, fluctuations in estrogen and progesterone during the menstrual cycle impact gene expression in hormone-responsive cancers. However, the extent to which menstrual cycling affects the Oncotype DX 21-gene signature remains unclear. Here, we investigate the impact of ovarian cycle stage on the 21-gene signature using a naturally cycling mouse model of breast cancer.MethodsER-positive mammary tumours were dissected from naturally cycling Mmtv-Pymt mice at either the estrus or diestrus phase of the ovarian cycle. The Oncotype DX 21-gene signature was assessed through quantitative real time-PCR, and a 21-gene experimental recurrence score analogous to the Oncotype DX Recurrence Score was calculated.ResultsTumours collected at diestrus exhibited significant differences in expression of 6 Oncotype DX signature genes (Ki67, Ccnb1, Esr1, Erbb2, Grb7, Bag1; p ≤ 0.05) and a significant increase in 21-gene recurrence score (21.8 ± 2.4; mean ± SEM) compared to tumours dissected at estrus (15.5 ± 1.9; p = 0.03). Clustering analysis revealed a subgroup of tumours collected at diestrus characterised by increased expression of proliferation- (p < 0.001) and invasion-group (p = 0.01) genes, and increased 21-gene recurrence score (p = 0.01). No correlation between ER, PR, HER2, and KI67 protein abundance measured by Western blot and abundance of mRNA for the corresponding gene was observed, suggesting that gene expression is more susceptible to hormone-induced fluctuation compared to protein expression.ConclusionsOvarian cycle stage at the time of tissue collection critically affects the 21-gene signature in Mmtv-Pymt murine mammary tumours. Further studies are required to determine whether Oncotype DX Recurrence Scores in women are similarly affected by menstrual cycle stage.
Highlights
The Oncotype DX 21-gene Recurrence Score assay is used in clinical practice for guiding adjuvant chemotherapy treatment decisions for women with early-stage, estrogen receptor (ER)-positive, Human epidermal growth factor receptor (HER2)-negative breast cancer [1,2,3,4]
The Oncotype DX assay quantifies the expression of 16 genes associated with proliferation (MKI67, Aurora Kinase A (STK15), Baculoviral IAP Repeat-Containing 5 (BIRC5), Cyclin B1 (CCNB1), Myb Proto-Oncogene Like 2 (MYBL2)), estrogen signalling (ESR1, Progesterone Receptor (PGR), B-Cell CLL/Lymphoma 2 (BCL2), Signal Peptide (SCUBE2)), HER2 (ERBB2, Growth Factor Receptor-Bound Protein 7 (GRB7)), invasion (MMP11, Cathepsin V (CSTV)) and other genes (GSTM1, BCL2-Associated Athanogene (BAG1), CD68 Molecule (CD68)), as well as 5 house-keeping genes
Mammary tumours dissected from mice at diestrus exhibit increased expression of proliferative and HER2-associated genes, and increased 21-gene experimental recurrence scores, compared to tumours dissected at estrus
Summary
The Oncotype DX 21-gene Recurrence Score assay is used in clinical practice for guiding adjuvant chemotherapy treatment decisions for women with early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer [1,2,3,4]. The Oncotype DX assay quantifies the expression of 16 genes associated with proliferation (MKI67, STK15, BIRC5, CCNB1, MYBL2), estrogen signalling (ESR1, PGR, BCL2, SCUBE2), HER2 (ERBB2, GRB7), invasion (MMP11, CSTV) and other genes (GSTM1, BAG1, CD68), as well as 5 house-keeping genes. These 21 signature genes are combined in an algorithm to calculate a Recurrence Score that reflects the patient’s underlying risk of disease recurrence and predicts the likely benefit from the addition of chemotherapy to endocrine treatment [5,6,7,8,9,10]. We investigate the impact of ovarian cycle stage on the 21-gene signature using a naturally cycling mouse model of breast cancer
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