Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer

Abstract

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27–35 and 1–6; low oestradiol and low progesterone), W2 (days 7–16; high oestradiol and low progesterone) and W3 (days 17–26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3–2.4-fold; FDR 0.016–0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.

Discordance in 21-gene recurrence scores between paired breast cancer samples is inversely associated with patient age

“…Likewise, progesterone treatment of breast cancer cell lines increases growth factor receptor signalling and Oncotype DX Recurrence Scores [24]. While it has also been reported that the expression of oestrogen-regulated genes fluctuates across the menstrual cycle [20][21][22][23] and that oestrogen and progesterone affect the invasive properties of premenopausal breast cancers [33][34][35], we did not observe variable expression of Oestrogen or Invasion group genes between paired breast cancer samples collected from younger women.…”

“…In premenopausal women, hormone receptor protein expression fluctuates throughout the menstrual cycle in response to fluctuating concentrations of oestrogen and progesterone and this is associated with downstream changes in the expression of a number of genes which are part of the Oncotype DX signature including PGR, MKI67, CCNB1, BIRC5 and MYBL2 [18][19][20][21][22][23]. Therefore, changes in gene expression with menstrual cycle stage could affect Oncotype DX Recurrence Scores.…”

WITHDRAWN: Genome-Wide DNA Methylome and Whole-Transcriptome Landscapes of Spontaneous Intraductal Papilloma in Tree Shrews (Tupaia Belangeri)

“…In primary breast cancers, PDZK1 is an oestrogen-regulated gene that is overexpressed in ER-positive breast cancers [27]. PDZK1 has been as a marker of oestrogen-regulated gene (ERG) expression in examining the relationship between the menstrual cycle and oestrogen receptor-positive breast cancer [28]. Dunbier et al further veri ed that the expression of PDZK1 was strongly related to plasma oestradiol (E2) levels in postmenopausal patients with primary ER-positive breast cancer [29].…”

90 YEARS OF PROGESTERONE: Progesterone receptor signaling in the normal breast and its implications for cancer

“…Furthermore, together with other studies it revealed that RANKL transcripts are also regulated in ER/PR+ tumors (Haynes et al, 2013(Haynes et al, , 2014. Interestingly, in the normal breast epithelium increased mitotic activity has been reported to occur during luteal phase when progesterone levels are high (Anderson et al, 1982;Ferguson & Anderson, 1981;Pardo et al, 2014), but ER+ tumors proliferation-associated genes were decreased when progesterone levels peaked (Haynes et al, 2014(Haynes et al, , 2019. It needs to be evaluated whether this discrepancy may be related to different experimental approaches or whether this is an indication that PR signaling and cell cycle control are wired differently in normal breast epithelial cells and cancer cells.…”