Hormonal Modulation of Breast Cancer Gene Expression: Implications for Intrinsic Subtyping in Premenopausal Women

Abstract

Clinics are increasingly adopting gene-expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumor. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and validated using breast cancer samples from postmenopausal women. Thus, the accuracy of such tests has not been explored in the context of the hormonal fluctuations in estrogen and progesterone that occur during the menstrual cycle in premenopausal women. Concordance between traditional methods of subtyping and the new tests in premenopausal women is likely to depend on the stage of the menstrual cycle at which the tissue sample is taken and the relative effect of hormones on expression of genes versus proteins. The lack of knowledge around the effect of fluctuating estrogen and progesterone on gene expression in breast cancer patients raises serious concerns for intrinsic subtyping in premenopausal women, which comprise about 25% of breast cancer diagnoses. Further research on the impact of the menstrual cycle on intrinsic breast cancer profiling is required if premenopausal women are to benefit from the new technology of intrinsic subtyping.

Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

“…However, if we performed DEA without correction for covariates, such as the level of immune infiltration, this number rose to 33 PAM50 genes, indicating that the lack of PAM50 genes in the corrected DE sets, was mainly a result of low power, perhaps in combination with differences between the TNBC subtypes and basallike cancers. Figure 6b shows that the expression directionality of PAM50 genes was in consensus with that of the literature and their potential role in (breast) cancer [105][106][107]. Eleven PAM50 genes had been annotated in the COSMIC cancer gene census, out of which seven (BCL2, CCNE1, EGFR, ERBB2, ESR1, FOXA1, and FOXC1) were found to be DE in our analysis, all with a consensus of cardinality between subtypes- Fig.…”

Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk

“…The relative expression of panels of genes, employed in tests such as Oncotype DX and Prosigna, classifies tumor subtype and predicts risk of disease recurrence, in order to guide treatment decision-making (101, 102). However, such tests were developed and validated largely in postmenopausal women, and the utility of these tests in premenopausal women might be affected by fluctuating estrogen and progesterone at different stages of the menstrual cycle (103). Overall, a clearer understanding of the molecular, cellular, and immunological changes that occur in the breast during the menstrual cycle could be fundamental for improving personalized and preventive programs in breast cancer.…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…More specifically they account 50-60% and 15-20% respectively (9). These subtypes are generally correlated to a good prognosis.…”