Research advances in the effects of propofol on breast cancer

Author: Miao Zhang, School of Anesthesiology, Shanxi Medical University; Yue Wei, Department of Anesthesiology, The Second Hospital of Shanxi Medical University

Breast cancer is the most common malignancy in women and is the second leading cause

Local recurrence or distant metastasis of the tumor after surgery is the leading cause

The results show that in addition to anesthesia, propofol also has antioxidant, inhibition of the body's inflammatory response, antiemetic, cancer suppression, analgesia and immune regulation

Clinical studies have shown that when the plasma concentration of targeted controlled infusion (TCI) during propofol anesthesia is 3~6μg/mL, it has a strong anti-invasion effect

1.

Breast cancer includes about twenty histological subtypes, according to the test results of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor2 (HER2), Breast cancer can be divided into four different subtypes

At present, scholars have established more than 51 breast cancer cell lines and successfully achieved in vitro culture, which is widely used to study the effects

1.

Li et al.

Ecimovic et al.

The TGF-β1 signaling pathway plays an important role

In some studies, the breast cancer cell line MDA-MB-231 was cultured in serum taken 24 hours after surgery in breast cancer patients, and it was found that the ability of cell lines to migrate was not affected

1.

Due to the large heterogeneity of each subtype of breast cancer, the dose and treatment time of propofol may vary

Other results show that the use of propofol (2~10μg/mL) for breast cancer MDA-MB-231 cell line for 12 h can promote the proliferation and migration of tumor cells.

2.

miRNA is a class of non-coding RNAs that have been shown to have endogenous regulatory functions in recent years, which can act on the 3' non-translated region (3'UTR) of the target mRNA to achieve the regulation
of gene expression at the post-transcriptional level.
Related studies have confirmed that abnormal miRNA function is related
to the occurrence and development of malignant tumors.
Studies have shown that miRNA-24 is upregulated in breast cancer tissues, and the expression of p27 is inversely correlated
with it.

Overexpression of miRNA-24 in breast cancer cell lines MDA-MB-435 and MDA-MB-468 can promote the proliferation of breast cancer cells and inhibit apoptosis
.
In addition, the findings show that miRNA-24 acts directly on the 3'UTR of p27, inhibits its expression, and promotes cell proliferation, while overexpression of p27 can reverse the above molecular biological processes
.
Propofol promotes apoptosis
in breast cancer cell lines by inhibiting the expression of miRNA-24 in MDA-MB-435 cell lines and upregulating p27 expression levels.

miRNA-21 promotes tumor cell proliferation
by activating the phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway (PI3K/Akt) signaling pathway of phosphatase and tensin homologous genes (PTEN genes) missing phosphatase on chromosome 10 。 Studies have shown that propofol inhibits the activation of PI3K/Akt and Wnt3α/β-catenin pathways by inhibiting the expression of miRNA-21 in the MCF-7 cell line of breast cancer, thereby inhibiting the proliferation of cells and the process
of epithelial-interstitial transformation reaction.
LncRNA is an endogenous RNA with a length of 200 to 100 000 nt, and invasion and metastasis of various tumors are related
to the abnormal expression of specific lncRNA.

The study found that lncRNA H19 is highly expressed in 72% of breast cancer tissues, which is mainly expressed in stromal cells or partially expressed in epithelial cells
.
Overexpression of lncRNA H19 in breast cancer MDAMB-231 cell lines can promote proliferation and migration
of cancer cells.
lncRNA H19 directly binds to the mRNA of CasitasB cell lymphoma protein c (Cbl-c) and CasitasB cell lymphoma protein b (Cbl-b) via miRNA-675 to enhance the stability and activity of epidermal growth factor receptor (EGFR) and intercellular interstitial epithelial conversion factor (c-Met), thereby continuously activating the Akt and extracellular regulatory protein kinase (Erk) signaling pathways, Promotes tumor cell proliferation and migration
.
Propofol reduces the invasion and migration capacity
of MDA-MB-231 cell line by downregulating the expression of lncRNA H19 in this cell line.

3.
Clinical study of propofol and breast cancer

Several studies have compared the effects
of propofol transintravenous anesthesia versus inhaled anesthesia on postoperative prognosis in breast cancer patients.
The results of studies have shown that the survival rate of patients receiving propofol anesthesia is higher than that of inhaled sevoflurane in both 1 and 5 years after surgery, but after eliminating the confounding factors (the proportion of patients with heart disease in the sevoflurane group is higher than that in the propofol group), propofol anesthesia has no significant advantage
in improving the postoperative survival rate of breast cancer patients.

Another study showed that although the postoperative tumor recurrence rate was lower in breast cancer patients in the propofol group, the difference in 5-year survival between the propofol group and the sevoflurane group was not statistically significant
.
CD39 and CD73 play an important role in tumor immunosuppression, promote tumor recurrence and metastasis, and regulatory T cells with high expression of CD39 and CD73 can inhibit the function of type 1 and 17 helper T cells and destroy the function of
tumor natural killer cells and cytotoxic T cells.

The results of a recent randomized controlled trial showed that propofol or sevoflurane anesthesia had a similar effect on the expression levels of regulatory T cells CD39 and CD73 in patients undergoing breast cancer surgery, similar
to the effect on the number of helper T cells, tumor natural killer cells and cytotoxic T cells in the patient's circulation.
Therefore, the effect of intraoperative propofol and sevoflurane anesthesia on immune cells in breast cancer patients may not be significantly different
.
In tumor surgery, the effect of anesthetics on perioperative immune function may be relatively small
.

Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous cells that are precursors to dendritic cells (DCs), macrophages, and/or granulocytes, with a significant inhibitory function of
immune cell response.
One study explored the effects of sevoflurane and propofol anesthesia on MDSC expression and prognosis in patients undergoing breast cancer surgery, and the results showed that there was no significant difference between propofol and sevoflurane anesthesia in serum MDSC expression and prognosis in breast cancer patients
.
Vascular endothelial growth factor (VEGF) and TGF-β play an important role
in tumor growth and metastasis.

Overexpression of VEGF-C in breast cancer cells can significantly increase intratumoral lymphangiogenesis, resulting in a significant increase in regional lymph node and lung metastases, while TGF-β can promote tumor growth and metastasis
.
Sevoflurane promotes angiogenesis, while propofol has anti-angiogenic effects
.
Studies have compared the effects of propofol and sevoflurane anesthesia on VEGF-C and TGF-β expression and prognosis in patients with breast cancer after surgery, and the results show that compared with sevoflurane inhalation anesthesia, intravenous anesthesia can effectively inhibit the release of VEGF-C induced by breast surgery, but has no significant effect on the short-term recurrence rate of breast cancer patients, and the difference between the two anesthetic drugs on TGF-β expression level is not statistically significant
.

In summary, most basic studies have concluded that propofol can inhibit the proliferation and migration
of breast cancer cells.
So far, the mechanism of action of propofol on breast cancer is still unclear, but the mechanism of action of propofol on different types of cancer cells can be referred to to simulate and study the possible molecular biological process
of propofol on breast cancer cells.

4.
Summary and outlook

The relationship between anesthesia strategy and the prognosis of tumor patients has become the focus
of academic attention.
At present, a large number of basic research suggests that compared with volatile anesthetics, propofol may help reduce the recurrence and metastasis of tumors in tumor patients after surgery, and the potential effect of propofol on breast cancer may be related to its mechanism of
inhibiting cancer cell migration, proliferation, and protecting the body's normal immune function.
However, the existing laboratory research data on the effect of propofol on breast cancer and the conclusions of clinical studies are not consistent
.

Most in vitro studies focused on analyzing the effects of propofol on behavioral changes in cancer cells without delve into its underlying mechanisms
.
In addition, most clinical studies are retrospective and lack a strong evidence-based basis to guide anesthesia practice
.
Therefore, possible mechanisms and protocols to prevent and/or eliminate the possible harmful effects
of certain anesthetics on breast cancer patients have yet to be further explored.

Source: Zhang Miao, Yue Wei.
Research progress on the effect of propofol on breast cancer[J].
Shanghai Medical Journal,2022,45(03):206-210.