This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about breast cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

We previously synthesized new tubulin inhibitors, MPT0B169 and MPT0B002, which induced growth inhibition and apoptosis in leukemia cells. However, their effects on solid tumor cells have not been determined. In this study, we investigated the effects of MPT0B169 and MPT0B002 on glioblastoma, breast, lung, and colorectal cancer (CRC) cell lines. A cell viability analysis showed that MPT0B169 and MPT0B002 were more effective in inhibiting the proliferation of COLO205 and HT29 CRC cells than U87MG and GBM8401 glioblastoma, MCF-7 and MDA-MB-231 breast cancer, and A549 lung cancer cells. MPT0B169 and MPT0B002 inhibited growth of COLO205 and HT29 cells in dose- and time-dependent manners. A colony-formation assay confirmed the growth inhibitory effects of MPT0B169 and MPT0B002 on COLO205 and HT29 cells. MPT0B169 and MPT0B002 disrupted tubulin polymerization and arrested the cell cycle at the G2/M phase, with a concomitant increase of the cyclin B1 level. MPT0B169 and MPT0B002 induced apoptosis, accompanied by induction of the intrinsic apoptotic pathway, as shown by a reduction in the caspase-9 level and increases in cleaved caspase-3 and cleaved PARP. These results suggest that MPT0B169 and MPT0B002, new tubulin inhibitors, induced growth inhibition, G2/M arrest, and apoptosis in COLO205 and HT29 cells, and they could potentially be anticancer agents for CRC cells.

Breast cancer is the second cause of death among women all around the world. One out of every eight women is diagnosed with breast cancer in Iran. There are many reasons for cancer, one of which is the mutations in the mitochondrial genome observed in most breast cancer studies. However, the aim of this study is to evaluate the genetic region of NADH dehydrogenase subunit 4 in patients with breast cancer. First, the genomic DNA was extracted from a tissue. The NADH dehydrogenase subunit 4 coding region was amplified by PCR, and then the SSCP was sequenced. After that, the molecular dynamics were employed. The association between the mutations and the prognostic factors such as ER, PR, HER-2, and age were statistically examined. The sequence of the ND4 area was determined in 24 suspected patients, and 15 nucleotide changes were reported. The role of this variations was investigated by in-silico. The harmful mutations were predicted based on some servers. The molecular dynamics results showed that there is a significant relationship between the mutant protein and the changes in the structural conformation. Our results showed that the mutation in the ND4 area plays an important role in developing breast cancer. So, it can be concluded that the mitochondrial NADH dehydrogenase analysis may help to detect breast cancer in the early stages.

Tumor-associated macrophages (TAMs) are important tumor-promoting cells in the breast tumor microenvironment. Preclinically TAMs stimulate breast tumor progression, including tumor cell growth, invasion and metastasis. TAMs also induce resistance to multiple types of treatment in breast cancer models. The underlying mechanisms include: induction and maintenance of tumor-promoting phenotype in TAMs, inhibition of CD8+ T cell function, degradation of extracellular matrix, stimulation of angiogenesis and inhibition of phagocytosis. Several studies reported that high TAM infiltration of breast tumors is correlated with a worse patient prognosis. Based on these findings, macrophage-targeted treatment strategies have been developed and are currently being evaluated in clinical breast cancer trials. These strategies include: inhibition of macrophage recruitment, repolarization of TAMs to an antitumor phenotype, and enhancement of macrophage-mediated tumor cell killing or phagocytosis. This review summarizes the functional aspects of TAMs and the rationale and current evidence for TAMs as a therapeutic target in breast cancer.

Human 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1 and 7 catalyze the final step of estrogen activation and the first step in androgen inactivation. It has been shown in breast cancer cells that DHT has a suppression effect on cell proliferation, counteracting the estrogen growth effect. However, the exact kinetic function of 17β-HSD7 in steroidogenesis was not determined. Here we report the steady-state kinetics and binding study for 17β-HSD7 with estrone or DHT as substrates and NADPH as cofactor. 17β-HSD7 has been overexpressed in E. coli and purified. For both substrates, kinetics of 17β-HSD7 demonstrates positive cooperativity. The K0.5 value is 5.2 ± 0.4 µM and 14.4 ± 0.8 µM and the kcat is 0.0063 ± 0.0003 s-1 and 0.0153 ± 0.0007 s-1 for the reduction of E1 and DHT, respectively. The binding study shows a similar affinity with a dissociation constant of 5.2 ± 0.5 µM and 11 ± 1 µM for E1 and DHT, respectively. Our kinetic and binding results reveal a positive cooperativity for 17β-HSD7 to both the E1 and DHT with a similar affinity, while 17β-HSD1 demonstrated a significantly higher affinity toward E1 than DHT, but with a strong E1 substrate inhibition. These results strongly support that the inhibition of 17β-HSD7 constitutes the basis of breast cancer cell proliferation decreasing that led to the shrinkage of xenograft ER + breast tumor mice model.

Hepsin is required for the growth and maintenance of normal morphology, as well as for cell motility and development, initiation of blood coagulation and pro-inflammatory immune response. Here we showed that Cathepsin D (CtsD) as a novel protein is involved in the regulation of hepsin. CtsD destabilizes hepsin by promoting its ubiquitylation and subsequent proteasomal degradation in breast cancer cells. Breast cancer tissue microarray also indicated that hepsin expression was negatively correlated with CtsD by immunohistochemistry. Overexpression of CtsD promoted breast cancer cell migration, invasion and metastasis by enhancing the expression of intercellular cell adhesion molecule-1 (ICAM-1) in vitro and in vivo. These effects were inhibited by ectopic hepsin expression. Taken together, our data reveal a critical CtsD-hepsin signaling axis in migration and metastasis, which may contribute to a better understanding of the function and molecular mechanism in breast cancer progression.

Triple-negative breast cancer (TNBC) is the most difficult subtype of breast cancer to treat due to a paucity of effective targeted therapies. Many studies have reported that breast cancer stem cells (BCSCs) are enriched in TNBC and are responsible for chemoresistance and metastasis. In this study, we identify LRP8 as a novel positive regulator of BCSCs in TNBC. LRP8 is highly expressed in TNBC compared to other breast cancer subtypes and its genomic locus is amplified in 24% of TNBC tumors. Knockdown of LRP8 in TNBC cell lines inhibits Wnt/β-catenin signaling, decreases BCSCs, and suppresses tumorigenic potential in xenograft models. LRP8 knockdown also induces a more differentiated, luminal-epithelial phenotype and thus sensitizes the TNBC cells to chemotherapy. Together, our study highlights LRP8 as a novel therapeutic target for TNBC as inhibition of LRP8 can attenuate Wnt/β-catenin signaling to suppress BCSCs.

Recently, sphingolipid derivatives, such as ceramide and sphingosine‑1‑phosphate (S1P), have emerged as key modulators in apoptotic cell death and cell proliferation. This study aimed to clarify the underlying signaling pathways of ceramide and S1P involved in breast cancer cell proliferation. Ceramide acyl chain length is determined by six mammalian ceramide synthases (CerS). We overexpressed CerS1 to 6 in MCF‑7 cells to examine whether ceramide signaling propagation varies as a function of acyl chain length. Among the six CerS, only CerS6 overexpression reduced phosphorylation of Akt, S6 kinase (S6K), and extracellular signal‑regulated kinases (ERK) as shown by western blotting. In addition, CerS6 overexpression reduced MCF‑7 cell proliferation. This effect was partially reversed by co‑treatment with MHY1485, an activator of mammalian target of rapamycin (mTOR), demonstrating an important role for the mTOR pathway in the CerS6‑mediated decrease in MCF‑7 cell proliferation. ERK inhibition, but not Akt inhibition, along with mTOR inhibition synergistically reduced MCF‑7 cell proliferation as measured by MTT assay. Notably, the expression of CerS6 and S1P receptor 2 (S1PR2), or CerS6 and sphingosine kinase 1 (SphK1), were negatively correlated according to the invasive breast carcinoma patient cohort in The Cancer Genome Atlas database. In addition, both SphK1 overexpression and S1P addition increased mTOR phosphorylation as shown by ELISA, while S1PR2 inhibition had the inverse effect. These data suggest that CerS6 and SphK1 regulate mTOR signaling in breast cancer cell proliferation. Moreover, mTOR activity can be regulated by the balance between S1P and C16‑ceramide, which is generated by CerS6.