Novel Melatonin, Estrogen, and Progesterone Hormone Therapy Demonstrates Anti-Cancer Actions in MCF-7 and MDA-MB-231 Breast Cancer Cells

Abstract

A novel melatonin, estrogen, and progesterone hormone therapy was developed as a safe bio-identical alternative hormone therapy for menopausal women based on the Women’s Health Initiative findings that PremPro™ increased breast cancer risk and mortality of all types of breast cancer in postmenopausal women. For HER2 breast cancer, melatonin, estrogen, and progesterone delayed tumor onset and reduced tumor incidence in neu female mice. For other breast cancers, its actions are unknown. In this study, melatonin, estrogen, and progesterone hormone therapy were assessed in human ER+ (MCF-7) and triple negative breast cancer (MDA-MB-231) cells, and found to decrease proliferation and migration of both breast cancer lines. Inhibition of MEK1/2 and 5 using PD98059 and BIX02189, respectively, inhibited proliferation and migration in MDA-MB-231 cells and proliferation in MCF-7 cells; however, when combined with melatonin, estrogen, and progesterone, BIX02189 blocked melatonin, estrogen, and progesterone–mediated inhibition of migration in MCF-7 cells and induced Elf-5. For MDA-MB-231 cells, BIX02189 combined with melatonin, estrogen, and progesterone inhibited proliferation and increased pERK1/2 and β1-INTEGRIN; levels of pERK5 remained low/nearly absent in both breast cancer lines. These findings demonstrate novel anti-cancer actions of melatonin, estrogen, and progesterone in ER+ and triple negative breast cancer cells through intricate MEK1/2- and MEK5-associated signaling cascades that favor anti-proliferation and anti-migration.

Insights into the Behavior of Triple-Negative MDA-MB-231 Breast Carcinoma Cells Following the Treatment with 17β-Ethinylestradiol and Levonorgestrel

“…Their response to chemotherapy is intermediate [ 46 ], MDA-MB-231 being a highly aggressive and invasive breast cancer model, both in vitro and in vivo [ 45 ]. The concentrations tested in this study (0.05, 1, and 10 µM) were selected based on a revision of the literature regarding the doses of EE, LNG, and EE-LNG tested previously in vitro [ 10 , 47 ].…”

“…5α-reductase is highly expressed in both hormone-responsive and -unresponsive BC cell lines [ 56 , 57 ], including MDA-MB-231 [ 58 ] which explains the increased cell viability caused by LNG. Hasan et al observed a dose-dependent stimulatory effect of estrogen and progesterone (1 pM, 1 nM, 100 nM, 1 µM, 10 µM) in MCF-7 cells after 24 h, while no concentration-dependent effects on the proliferation of MDA-MB-231 cells [ 47 ].…”

Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

“…Often, patients with cancer experience chronic fatigue, anemia, depression, and overall decreased quality of life. Researchers recognized that individuals with solid tumors have an initial immune response involving pro-inflammatory cytokines as the body recognizes self from non-self [ 189 ]. During this process, the kynurenic pathway is accelerated, causing inflammation-mediated tryptophan catabolism, fatigue, anemia, and depression [ 190 ].…”

Melatonin Regulates the Daily Levels of Plasma Amino Acids, Acylcarnitines, Biogenic Amines, Sphingomyelins, and Hexoses in a Xenograft Model of Triple Negative Breast Cancer

“…More recently, studies focused on combination therapy using melatonin have documented a potent inhibitory action on MDA-MB-231 cells. Hasan et al [ 48 ] reported that melatonin, estrogen, and progesterone led to significant inhibition of cell proliferation. In a HER2-positive BC mice model, these compounds delayed tumor onset while lowering its incidence.…”