TNBC (Triple Negative Breast Cancer) is a subtype of breast cancer with an aggressive phenotype which shows high metastatic capability and poor prognosis. Owing to its intrinsic properties like heterogeneity, lack of hormonal receptors and aggressive phenotype leave chemotherapy as a mainstay for the treatment of TNBC. Various studies have demonstrated that chemotherapy alone or therapeutic drugs targeting TNBC pathways, epigenetic mechanisms and immunotherapy alone have not shown significant improvement in TNBC patients. On the other hand, a combination of therapeutic drugs or addition of chemotherapy with therapeutic drugs has shown substantial improvement in results and proven to be an effective strategy for TNBC treatment. This review sheds light on effective combinational drug strategies and current clinical trial status of various combinatorial drugs for the treatment of TNBC.

The Nuclear Factor Kappa B (NF-κB) transcription factor family consists of five members: RelA (p65), RelB, c-Rel, p50 (p105/NF-κB1), and p52 (p100/NF-κB2). This family is considered a master regulator of classical biochemical pathways such as inflammation, immunity, cell proliferation, and cell death. The proteins in this family have a conserved Rel homology domain (RHD) with the following subdomains: DNA binding domain (RHD-DBD) and dimerization domain (RHD-DD). Despite the importance of the NF-κB family in biology, there is a lack of information with respect to their distribution patterns, evolution, and structural conservation concerning domains and subdomains in animals. This study aims to address this critical gap regarding NF-κB proteins. A comprehensive analysis of NF-κB family proteins revealed their distinct distribution in animals, with differences in protein sizes, conserved domains, and subdomains (RHD-DBD and RHD-DD). For the first time, NF-κB proteins with multiple RHD-DBDs and RHD-DDs have been identified, and in some cases, this is due to subdomain duplication. The presence of RelA/p65 exclusively in vertebrates shows that innate immunity originated in fishes, followed by amphibians, reptiles, aves, and mammals. Phylogenetic analysis showed that NF-κB family proteins grouped according to animal groups, signifying structural conservation after speciation. The evolutionary analysis of RHDs suggests that NF-κB family members p50/p105 and c-Rel may have been the first to emerge in arthropod ancestors, followed by RelB, RelA, and p52/p100.

Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and histone deacetylation complex, is widely up-regulated in human cancers and correlates with tumor metastasis, its regulatory mechanism and related signaling pathways remain unknown. Here, we report a previously unrecognized bidirectional autoregulatory loop between MTA1 and tumor suppressor alternative reading frame (ARF). MTA1 transactivates ARF transcription by recruiting the transcription factor c-Jun onto the ARF promoter in a p53-independent manner. ARF, in turn, negatively regulates MTA1 expression independently of p53 and c-Myc. In this context, ARF interacts with transcription factor specificity protein 1 (SP1) and promotes its proteasomal degradation by enhancing its interaction with proteasome subunit regulatory particle ATPase 6, thereby abrogating the ability of SP1 to stimulate MTA1 transcription. ARF also physically associates with MTA1 and affects its protein stability. Thus, MTA1-mediated activation of ARF and ARF-mediated functional inhibition of MTA1 represent a p53-independent bidirectional autoregulatory mechanism in which these two opposites act in concert to regulate cell homeostasis and oncogenesis, depending on the cellular context and the environment.

Although p21-activated kinase 1 (PAK1) and microtubule (MT) dynamics regulate numerous fundamental processes including cytoskeleton remodeling, directional motility, and mitotic functions, the significance of PAK1 signaling in regulating the functions of MT-destabilizing protein mitotic centromere-associated kinesin (MCAK) remains unknown. Here we found that MCAK is a cognate substrate of PAK1 wherein PAK1 phosphorylates MCAK on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that PAK1 phosphorylation of MCAK on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes, respectively, in the mammalian cells.

Microrchidia family CW‐type zinc finger 2 (MORC2) is a recently identified chromatin modifier with an emerging role in cancer metastasis. However, its role in glucose metabolism, a hallmark of malignancy, remains to be explored. We found that MORC2 is a glucose‐inducible gene and a target of c‐Myc. Our meta‐analysis revealed that MORC2 expression is positively correlated with the expression of enzymes involved in glucose metabolism in breast cancer patients. Furthermore, overexpression of MORC2 in MCF‐7 and BT‐549 cells augmented the expression and activity of a key glucose metabolism enzyme, lactate dehydrogenase A (LDHA). Conversely, selective knockdown of MORC2 by siRNA markedly decreased LDHA expression and activity and in turn reduced cancer cell migration. Collectively, these findings provide evidence that MORC2, a glucose‐inducible gene, modulates the migration of breast cancer cells through the MORC2–c‐Myc–LDHA axis.