Breast cancer, the most common malignancy in women worldwide, is a very heterogeneous disease. The different molecular profiles can be divided into three main subtypes according to hormone receptor (ER and PR) and HER2 (ERBB2) status. Screening is the most important tool in the fight against the disease. More molecular biomarkers are needed to improve diagnostic and therapeutic approaches.
Breast carcinoma is divided into luminal ER-positive and PR-positive breast carcinoma, which can be further classified into luminal A and B carcinoma, HER2-positive and triple negative breast carcinoma (TNBC). The most important means of reducing mortality among those affected is screening. Conventional chemotherapy and radiation therapy, which often includes targeted agents, is the main systemic treatment for breast cancer patients. However, many develop drug resistance, relapse, and secondary metastases. Thanks to improved multimodality therapy, early breast cancer (BC) is considered curable in 70-80% of patients, while advanced metastatic BC remains an unresolved challenge. Numerous studies are ongoing and efforts are being made to identify new molecular biomarkers to improve diagnostic and therapeutic approaches.
Exciting study approaches at a glance
Of note, a study that analyzed the TCGA/GTEx datasets available in GEPIA2 and used the tissue microarray of a cohort of 252 samples showed that breast cancer patients with higher levels of methionine adenosyltransferases 2 (MAT2A) and no MAT1A had poorer survival. The authors found that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poorer overall survival, and a MAT2A C/N expression ratio ≥1.0 was determined to be an independent risk factor by Cox regression analysis.
Using transcriptomic mapping of cyclin-dependent kinases (CDKs), CDK9 expression was shown to predict an adverse outcome in basal breast cancer and particularly in luminal B subtype with HER2+ expression. The scientists found that a novel proteolysis chimera (PROTAC) targeting CDK9, THAL-SNS-032, showed potent antitumor activity in breast cancer cell lines expressing both ER and HER2, such as BT474. Interestingly, drug-resistant cells from the BT474 cell line with resistance to trastuzumab, to the antibody-drug conjugate TDM1, or to the kinase inhibitor lapatinib showed particular sensitivity to THALSNS-032. Conversely, low doses of the drug caused severe toxicity in BT474 xenografts, particularly in gastrointestinal epithelium, without significant reduction in tumor volume, demonstrating its inverse therapeutic index.
A research group reported a synergistic antitumor effect of ruxolitinib (an orally administered selective inhibitor of Janus kinases 1 and 2) and calcitriol in HER2-enriched and triple-negative subtypes of breast cancer cells. The combined treatment caused inhibition of cell proliferation, induction of apoptosis, slowing of the cell cycle, and alteration of the expression of cell signaling proteins underlying these mechanisms. Similar results were obtained in vivo with ruxolitinib and calcitriol, which showed a synergistic inhibitory effect on tumor growth in MDA-MB-468 xenografts, confirming in vitro observations on the potential of this treatment in certain subtypes of breast cancer.
To improve the selectivity and bioavailability of chemotherapeutic agents, such as the class of platinum complexes, and overcome multiple mechanisms of drug resistance, researchers synthesized a novel imidazole-platinum(II) complex conjugated to a second-generation polyamidoamine (PAMAM) dendrimer (PtMet2-PAMAM). They showed that this compound increased apoptosis via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) and induced autophagy by activating the p38 pathway in various breast cancer cells. In addition, the complex inhibited drug efflux transporters and its positive charge increased uptake into tumor cells, demonstrating the ability of PtMet2-PAMAM to reverse multidrug resistance.
The future is individual
In summary, the studies show that by deepening our knowledge of the molecular mechanisms associated with drug resistance and underlying tumor progression, the future of BC research is reaching a point where treatments can be tailored to each individual patient.
Further reading:
- Zannetti A: Breast Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0. Int J Mol Sci 2023 Jan 29; 24(3): 2542.
- Loibl S, Poortmans P, Morrow M, et al: Breast cancer. Lancet 2021; 397: 1750.
- Chu PY, Wu HJ, Wang SM, et al: MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients. Int J Mol Sci 2021; 22: 5382.
- Noblejas-López MDM, Gandullo-Sánchez L, Galán-Moya EM, et al: Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer. Int J Mol Sci 2022; 23: 5476.
- Schneider J, Jeon YW, Suh YJ, Lim ST: Effects of Ruxolitinib and Calcitriol Combination Treatment on Various Molecular Subtypes of Breast Cancer. Int J Mol Sci 2022; 23: 2535.
- Czarnomysy R, Muszyńska A, Rok J, et al: Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells. Int J Mol Sci 2021; 22: 5581.
InFo ONCOLOGY & HEMATOLOGY 2023, 11(4): 40.
