Abstract
Simple SummaryBreast cancer remains the most commonly diagnosed cancer and the leading cause of cancer death among females worldwide. It is a highly heterogeneous disease, classified according to hormone and growth factor receptor expression. Patients with triple negative breast cancer (TNBC) (estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor (HER2)-negative) and hormone-independent HER2 overexpressing subtypes still represent highly aggressive behavior, metastasis, poor prognosis, and drug resistance. Thus, new alternative anticancer agents based on the use of natural products have been receiving enormous attention. In this regard, curcumin is a promising lead in cancer drug discovery due its ability to modulate a diverse range of molecular targets and signaling pathways. The current review has emphasized the underlying mechanism of curcumin anticancer action mediated through the modulation of PI3K/Akt/mTOR, JAK/STAT, MAPK, NF-ĸB, p53, Wnt/β-catenin, apoptosis, and cell cycle pathways in hormone-independent breast cancer, providing frameworks for future studies and insights to improve its efficiency in clinical practice.Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Despite the overall successes in breast cancer therapy, hormone-independent HER2 negative breast cancer, also known as triple negative breast cancer (TNBC), lacking estrogens and progesterone receptors and with an excessive expression of human epidermal growth factor receptor 2 (HER2), along with the hormone-independent HER2 positive subtype, still remain major challenges in breast cancer treatment. Due to their poor prognoses, aggressive phenotype, and highly metastasis features, new alternative therapies have become an urgent clinical need. One of the most noteworthy phytochemicals, curcumin, has attracted enormous attention as a promising drug candidate in breast cancer prevention and treatment due to its multi-targeting effect. Curcumin interrupts major stages of tumorigenesis including cell proliferation, survival, angiogenesis, and metastasis in hormone-independent breast cancer through the modulation of multiple signaling pathways. The current review has highlighted the anticancer activity of curcumin in hormone-independent breast cancer via focusing on its impact on key signaling pathways including the PI3K/Akt/mTOR pathway, JAK/STAT pathway, MAPK pathway, NF-ĸB pathway, p53 pathway, and Wnt/β-catenin, as well as apoptotic and cell cycle pathways. Besides, its therapeutic implications in clinical trials are here presented.
Highlights
Cancer as the complex disease is a major cause of morbidity and mortality around the world, with 9.9 million deaths in 2020, and has been considered as the world’s biggest killer by the age of 70 years in most countries in 2019
The findings suggested that curcumin induced the inhibition of STAT3 phosphorylation and inhibited its translocation into the nucleus, which resulted in a slightly reduced NFĸB-STAT3 protein interaction and downregulation of CD44 as the marker of cancer stem cell phenotype
In vitro and in vivo results obtained from a former study indicated that the sensitization of curcumin-treated breast cancer cells to paclitaxel and cyclophosphamide was mediated through the inhibition of NF-κB (p50 and p65), protein kinase C (PKC), histone deacetylase (HDAC), and telomerase activity in MDA-MB-231 cells and a breast cancer mouse model [121]
Summary
Cancer as the complex disease is a major cause of morbidity and mortality around the world, with 9.9 million deaths in 2020, and has been considered as the world’s biggest killer by the age of 70 years in most countries in 2019. TNBC has a highly aggressive clinical behavior, prone to earlier relapses and often metastasis to the brain and lungs correlated with poorer overall survival compared with other subtypes. This subgroup is difficult to treat and fails to respond to hormonal therapies or those targeting the HER2 receptors [17,18,19]. Curcumin is the major bioactive constituent of the turmeric spice derived from the rhizome of the plant Curcuma longa L It has been widely used in traditional Indian medicine (Ayurveda) for the treatment of a variety of diseases for at least 4000 years [24,25]. Cancers 2021, 13, 3427 known as TNBC (ER-, PR-, HER2-), while SKBR-3 and MDA-MB-453 are categorized as hormone-independent HER2 positive breast cancer (ER-, PR-, HER2+) subtypes
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