Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heterogeneity within the TNBC subtype, and studies have focused on genetic targets with high rates of altered expression. Recent studies suggest clear possibilities for benefits from targeted therapy in TNBC. In this review, we summarize studies of targeted therapy, including within mouse models, and discuss their applications in the development of combinatorial treatments to treat TNBC.

Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARHGAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR-200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess. .

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Pituitary tumor transforming gene (PTTG1, securin) is involved in cell-cycle control through inhibition of sister-chromatid separation. Elevated levels of PTTG1 were found to be associated with many different tumor types that might be involved in late stage tumor progression. However, the role of PTTG1 in early stage of tumorigenesis is unclear. Here we utilized the adenovirus expression system to deliver PTTG1 into normal human fibroblasts to evaluate the role of PTTG1 in tumorigenesis. Expressing PTTG1 in normal human fibroblasts inhibited cell proliferation. Several senescence-associated (SA) phenotypes including increased SA-␤-galactosidase activities, decreased bromodeoxyuridine incorporation, and increased SA-heterochromatin foci formation were also observed in PTTG1-expressing cells, indicating that PTTG1 overexpression induced a senescent phenotype in normal cells. Significantly, the PTTG1-induced senescence is p53-dependent and telomerase-independent, which is distinctively different from that of replicative senescence. The mechanism of PTTG1-induced senescence was also analyzed. Consistent with its role in regulating sister-chromatid separation, overexpression of PTTG1 inhibited the activation of separase. Consequently, the numbers of cells with abnormal nuclei morphologies and chromosome separations were increased, which resulted in activation of the DNA damage response. Thus, we concluded that PTTG1 overexpression in normal human fibroblasts caused chromosome instability, which subsequently induced p53-dependent senescence through activation of DNA-damage response pathway.

Current therapeutic outcomes for breast cancer underscore the complexity of treating a heterogeneous disease. Indeed, studies have shown that differences in gene expression among patients with the same subtype of breast cancer are correlated with the response to treatment. This strongly suggests that there is an urgent need to treat breast cancer with a personalized approach. Here we employed cell signaling pathway signatures to predict pathway activity in subtypes of MMTV-Myc mammary tumors. We then split tumors into subsets and developed individualized combinatorial treatments for two subtypes with distinct pathway activation patterns. Elevation of the EGFR, RAS and TGFβ pathways was observed in one subtype whereas these pathways were not predicted to be active in the other subtype that had high predicted activity of the Myc, Stat3 and Akt pathways. In a proof-of-principle experiment, treatment of these two subtypes with targeted therapies inhibited tumor growth only in the subtype of tumor where the therapy was designed to be active. We then analyzed gene expression profiles of human breast cancer patients and patient-derived xenograft (PDX) samples to predict pathway activity, and validated our approach of developing individualized treatments in mice with PDX tumors. Importantly, our combinatorial therapy resulted in tumor regression, including regression in PDX samples from triple-negative breast cancer. Together our data is a proof-of-principle experiment that demonstrates that cell signaling pathway signature-guided treatment for breast cancer is viable.

This study provides the first evidence that PTTG1 is involved in the early stages of oral tumorigenesis. Carcinogen exposure may cause the initial induction of PTTG1 expression in oral precancerous lesions. PTTG1 overexpression is a potential prognosticator for malignant progression of oral precancerous lesions.

Elevated Myc expression has been noted in basal breast cancer but therapies targeting Myc directly are lacking. It is therefore critical to characterize the interaction of Myc with other genes and pathways to uncover future potential therapeutic strategies. In this study, we bioinformatically predicted a role for Stat3 in Myc induced mammary tumors and tested it using mouse models. During normal mammary function, loss of Stat3 in Myc transgenic dams resulted in lethality of pups due to lactation deficiencies. We also observed that deletion of Stat3 in the mammary glands of MMTV-Myc mice unexpectedly resulted in increased and earlier hyperplasia and expedited tumorigenesis. However, despite arising earlier, Myc tumors lacking Stat3 grew more slowly with alterations in the resulting histological subtypes, including a dramatic increase in EMT-like tumors. We also observed that these tumors had impaired angiogenesis and a slight decrease in lung metastases. This metastatic finding is distinct from previously published findings in both MMTV-Neu and MMTV-PyMT mouse models. Together, the literature and our current research demonstrate that Stat3 can function as an oncogene or as a tumor repressor depending on the oncogenic driver and developmental context.