Triple-negative breast cancer: is there a treatment on the horizon?

Abstract

Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non-TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC.

Keywords: breast cancer; therapeutics; triple-negative.

Figure 1. Origin of triple-negative and basal-like breast cancers

Non-triple-negative basal-like breast cancer (NTN-BLBC) and triple-negative basal-like breast cancer (TN-BLBC) originate from basal-like breast cancer (BLBC) depending on whether HER2 amplification/mutation occurs in ER/PR-negative cancers following BRCA mutation. Non-basal-like triple-negative breast cancer (NB-TNBC) may originate from non-basal-like breast cancer (Non-BLBC) without BRCA mutation. Adapted from de Ruijter TC et al: J Cancer Res Clin Oncol 2011;137:183-192.

Figure 2. Inhibition of the cholesterol biosynthetic pathway by lovastatin

HMG-CoA: 3-hydroxy-3-methyl-glutaryl coenzyme A.

Figure 3. GO enrichment analysis of proteins regulated by lovastatin in MDA-MB-231 cells

MDA-MB-231 cells were treated with lovastatin or vehicle under hypoxia for 48 h and subjected to antibody microarray analysis followed by GO enrichment analysis as described in ref. [85]. A complete list of proteins regulated by lovastatin in MDA-MB-231 cells is available in that reference.

Figure 4. Summary of the potential agents under development for the treatment of triple-negative breast cancer

Microtubule stabilizers polymerize tubulin in the microtubule, thereby inhibiting cell division. Anthracyclines inhibit RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly growing cancer cells. Platinums generate intra- and inter-strand double-stranded DNA crosslinks, preventing the formation of the replication fork and inhibiting cell division. PARP inhibitors prevent the repair of single-strand breaks that occur during cell cycle especially in BRCA-mutated cells. Angiogenesis inhibitors block the growth of new blood vessels by inhibiting VEGF. EGFR inhibitors bind to EGFR and turn off the uncontrolled growth of cancer cells with EGFR mutations. TK inhibitors block tumor growth through inhibiting intracellular tyrosine kinase activity. mTOR inhibitors suppress cancer cell growth and proliferation through targeting the PI3K/Akt/mTOR signaling pathway. Statins inhibit the conversion of HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. The anti-cancer effects of statins may involve the inhibition of multiple signaling pathways important for the malignant phenotype of cancer cells. EGFR, epidermal growth factor receptor; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; mTOR, mammalian target of rapamycin; PARP, poly(ADP-ribose) polymerase; TK, tyrosine kinase.