Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches

Abstract

Breast cancer (BC) affects over 250,000 women in the US each year. Drug-resistant cancer cells are responsible for most breast cancer fatalities. Scientists are developing novel chemotherapeutic drugs and targeted therapy combinations to overcome cancer cell resistance. Combining drugs can reduce the chances of a tumor developing resistance to treatment. Clinical research has shown that combination chemotherapy enhances or improves survival, depending on the patient's response to treatment. Combination therapy is a highly successful supplemental cancer treatment. This review sheds light on intrinsic resistance to BC drugs and the importance of combination therapy for BC treatment. In addition to recurrence and metastasis of BC, the article discussed biomarkers for BC.

Keywords: Breast cancer; breast cancer biomarkers; breast cancer metastasis; breast cancer recurrence; combination therapies; intrinsic/acquired resistance.

Figure 1

This figure depicts the common locations of breast cancer metastases. Breast cancer can spread to bones, axillary lymph nodes, the liver, and the lungs. A tiny fraction of breast tumors can spread to the inner mammary gland, accounting for 10% to 40% of cases. Breast cancer can spread to different body regions based on the molecular subtype. When comparing luminal tumors to TNBC, lymphatic dissemination in TNBC is less common than in luminal malignancies.

Figure 2

A. Illustrates the Extrinsic and intrinsic factors such as extracellular matrix proteins, P-gp pump and ABC transporter efflux, and cytochrome P450 and glutathione transferases that are involved in the pathogenesis of cancer. B. Resistance to anticancer drugs can be caused by several mechanisms. As shown in the diagram above, cancer cells can survive and relapse in multiple ways. The mechanism includes MDR1 and MRP genes, miRNAs, CSCs, TME, Hypoxia, Cell cycle checkpoints, Drug uptake, DNA repair, Apoptosis, Drug metabolism, Stress response, and microbiota important mechanisms.

Figure 3

Both HER2 truncation and epitope masking reduce the amount of trastuzumab that can bind to HER2 in breast cancer. PI3K/Akt activity is also increased, and the Phosphodiesterase 1 (PDK1) gene has been changed. These pathways are being triggered at a considerably higher pace than they were previously. The immune system is also impaired.

Figure 4

HER2 is a cancer-causing gene with four membrane tyrosine kinase receptors (HER1-HER4), a molecular switch, and more than ten ligands. Ligand binding causes a conformational change in HER1, HER3, and HER4 that facilitates homo- or heterodimerization with another family member. HER2, which is gene-amplified and/or overexpressed in 20% of breast cancers, lacks a ligand and lies in an open conformation in the membrane. Due to its heterodimerization capability and increased expression, HER2 activates itself by homodimerizing with other ligand-bound HER members. In response to dimerization of the HER receptors, their TKs are activated. This initiates a phosphorylation cascade, which triggers downstream signaling pathways, including Ras/p42/44 MAPK and PI3K/AKT. By modifying and phosphorylating transcription factors and other parts of the transcription and cell-cycle machinery, downstream kinases stimulate the transcriptional and cell-cycle machinery. As a result, tumor cells can be stimulated to proliferate, survive, become angiogenic, and metastatic. Because HER3’s TK is inactive (X), the downstream signaling pathway can only be activated by heterodimerization with other HER members. According to the FDA, the HER2-targeted drugs approved for treating HER2+ breast cancer are trastuzumab, pertuzumab, trastuzumab DMT-1, and lapatinib.