Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk

Abstract

Fluctuations in circulating estrogen and progesterone across the menstrual cycle lead to increased breast cancer susceptibility in women; however, the biological basis for this increased risk is not well understood. Estrogen and progesterone have important roles in normal mammary gland development, where they direct dynamic interactions among the hormonally regulated mammary epithelial, stromal, and immune cell compartments. The continuous fluctuations of estrogen and progesterone over a woman’s reproductive lifetime affect the turnover of mammary epithelium, stem cells, and the extracellular matrix, as well as regulate the phenotype and function of mammary stromal and immune cells, including macrophages and regulatory T cells. Collectively, these events may result in genome instability, increase the chance of random genetic mutations, dampen immune surveillance, and promote tolerance in the mammary gland, and thereby increase the risk of breast cancer initiation. This article reviews the current status of our understanding of the molecular and the cellular changes that occur in the mammary gland across the menstrual cycle and how continuous menstrual cycling may increase breast cancer susceptibility in women.

A Longitudinal Study of the Association between Mammographic Density and Gene Expression in Normal Breast Tissue

“…This is in contrast to the low number of differentially expressed genes between breast biopsies from post-and pre/peri-menopausal women at a genome-wide level which has also been reported from other studies [60,69]. The low number of genes whose expression correlated to MD in pre/peri-menopausal women may be a reflection of more heterogeneity in genes relevant for MD as these may fluctuate substantially due to hormonal changes through the menstrual cycle, potentially masking such associations [70].…”

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To Dna Mutations

“…The female breast is a tissue that changes during different biological stages; in young women, the constant fluctuations of steroid hormones over a lifetime affect mammary tissue, which contains a high amount of enriched immature mammary cell populations (stem cells and progenitors), that increase during pregnancy and breastfeeding 32 . Collectively, these events might raise the risk of BC transformation through genome instability, increasing the probability of random genetic mutations and reducing immune surveillance 32 . Reproductive history impacts the prognosis of YWBC; in this regard, patients diagnosed within the next 5 years postpartum have a worse prognosis than nulliparous women or than those diagnosed during pregnancy 33 .…”

The effect of timing of breast cancer surgery during the menstrual cycle phase on the axillary lymph node, estrogen receptor, progesterone receptor and c-erb B2

“…Continuous uctuations of estrogen and progesterone throughout the reproductive period in women affect the phenotype and function of breast, stromal and immune cells including macrophages and regulatory T cells, as well as the turnover of the mammary epithelium, stem cells, and extracellular matrix. Collectively, these events can lead to genome instability, increase the likelihood of random genetic mutations, reduce immune supervision and increase tolerance in the mammary gland; thus increasing the risk of breast cancer onset [20]. In addition, uctuations in estrogen and progesterone throughout the menstrual cycle direct the proliferation, differentiation and apoptosis in the mammary gland epithelium [21].…”

“…Estrogen exerts proliferative effects on mammary epithelial channels by direct ERs, as well as upregulates the expression of PR during the luteal phase of the cycle [20]. ER, PR and c-ERBB2 (HER-2/neu) are important therapeutic and prognostic markers for breast carcinoma [22].…”