Metformin-induced downregulation of c-Met is a determinant of sensitivity in MDA-MB-468 breast cancer cells.

Metformin, the widely used anti-diabetic drug, is emerging as a promising anti-cancer agent. However, response variation among different tumors remains a significant challenge. Hence, identification of the factors that determine metformin sensitivity is of greatest significance for its clinical implementation.

FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells.

Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance.

FGFR1 overexpression renders breast cancer cells resistant to metformin through activation of IRS1/ERK signaling.

Metformin has been suggested as an anti-cancer agent. However, increasing reports show that some tumors are resistant to metformin. Identification of factors affecting metformin mediated cancer therapy is of great significance.

In Utero Exposure to Bisphenol a Promotes Mammary Tumor Risk in MMTV-Erbb2 Transgenic Mice Through the Induction of ER-erbB2 Crosstalk.

Bisphenol A (BPA) is the most common environmental endocrine disrupting chemical. Studies suggest a link between perinatal BPA exposure and increased breast cancer risk, but the underlying mechanisms remain unclear. This study aims to investigate the effects of in utero BPA exposure on mammary tumorigenesis in MMTV-erbB2 transgenic mice.

Bisphenol AF promotes estrogen receptor-positive breast cancer cell proliferation through amphiregulin-mediated crosstalk with receptor tyrosine kinase signaling.

Exposure to bisphenol A (BPA), an endocrine-disrupting compound, is associated with increased risk of estrogen-related diseases, including estrogen receptor-positive (ER+) breast cancer. Although bisphenol analogs, i.e.

Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues.

Caloric intake influences the onset of many diseases, including cancer. In particular, caloric restriction (CR) has been reported to suppress mammary tumorigenesis in various models. However, the underlying cancer preventive mechanisms have not been fully explored.

DMBA promotes ErbB2‑mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability.

Environmental factors, including 7,12‑dimethylbenz[a]anthracene (DMBA) exposure, and genetic predisposition, including ErbB2 overexpression/amplification, have been demonstrated to increase breast cancer susceptibility. Although DMBA‑ and ErbB2‑mediated breast cancers are well‑studied in their respective models, key interactions between environmental and genetic factors on breast cancer risk remain unclear. Therefore, the present study aimed to investigate the effect of DMBA exposure on ErbB2‑mediated mammary tumorigenesis.

Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells.

Although ErbB2-targeted therapeutics have significantly improved ErbB2 breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization.

Phenformin inhibits growth and epithelial-mesenchymal transition of ErbB2-overexpressing breast cancer cells through targeting the IGF1R pathway.

Reports suggest that metformin, a popular anti-diabetes drug, prevents breast cancer through various systemic effects, including insulin-like growth factor receptor (IGFR) regulation. Although the anti-cancer properties of metformin have been well-studied, reports on a more bioavailable/potent biguanide, phenformin, remain sparse. Phenformin exerts similar functional activity to metformin and has been reported to impede mammary carcinogenesis in rats.

Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells.

Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer.

FGFR inhibitor, AZD4547, impedes the stemness of mammary epithelial cells in the premalignant tissues of MMTV-ErbB2 transgenic mice.

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) regulates signaling pathways involved in cell proliferation and differentiation. Currently, the anti-tumor properties of FGFR inhibitors are being tested in preclinical and clinical studies. Nevertheless, reports on FGFR inhibitor-mediated breast cancer prevention are sparse.

Ganetespib induces G2/M cell cycle arrest and apoptosis in gastric cancer cells through targeting of receptor tyrosine kinase signaling.

Heat shock protein 90 (HSP90) regulates several important cellular processes via its repertoire of 'client proteins'. These client proteins have been found to play fundamental roles in signal transduction, cell proliferation, cell cycle progression and survival, as well as other features of malignant cells, such as invasion, tumor angiogenesis and metastasis. Thus, HSP90 is an emerging target for cancer therapy.

p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells.

Alcohol consumption is associated with increased breast cancer risk; however, the underlying mechanisms that contribute to mammary tumor initiation and progression are unclear. Alcohol is known to induce oxidative stress and DNA damage; likewise, p53 is a critical modulator of the DNA repair pathway and ensures genomic integrity. p53 mutations are frequently detected in breast and other tumors.

Buformin inhibits the stemness of erbB-2-overexpressing breast cancer cells and premalignant mammary tissues of MMTV-erbB-2 transgenic mice.

Background: Metformin, an FDA-approved drug for the treatment of Type II diabetes, has emerged as a promising anti-cancer agent. Other biguanide analogs, including buformin and phenformin, are suggested to have similar properties. Although buformin was shown to reduce mammary tumor burden in carcinogen models, the anti-cancer effects of buformin on different breast cancer subtypes and the underlying mechanisms remain unclear.

Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice.

Background: Although chemopreventative agents targeting the estrogen/estrogen receptor (ER) pathway have been effective for ER breast cancers, prevention of hormone receptor-negative breast cancers, such as Her2/erbB-2 breast cancers, remains a significant issue. Previous studies have demonstrated that administration of EGFR/erbB-2-targeting lapatinib to MMTV-erbB-2 transgenic mice inhibited mammary tumor development. The prevention, however, was achieved by prolonged high dose exposure.

Androgen receptor regulation by histone methyltransferase Suppressor of variegation 3-9 homolog 2 and Melanoma antigen-A11.

Androgen receptor (AR) transcriptional activity depends on interactions between the AR NH-terminal region and transcriptional coregulators. A yeast two-hybrid screen of a human testis library using predicted α-helical NH-terminal fragment AR-(370-420) as bait identified suppressor of variegation 3-9 homolog 2 (SUV39H2) histone methyltransferase as an AR interacting protein. SUV39H2 interaction with AR and the AR coregulator, melanoma antigen-A11 (MAGE-A11), was verified in two-hybrid, in vitro glutathione S-transferase affinity matrix and coimmunoprecipitation assays.

Up-Regulation of Follistatin-Like 1 By the Androgen Receptor and Melanoma Antigen-A11 in Prostate Cancer.

Background: High affinity androgen binding to the androgen receptor (AR) activates genes required for male sex differentiation and promotes the development and progression of prostate cancer. Human AR transcriptional activity involves interactions with coregulatory proteins that include primate-specific melanoma antigen-A11 (MAGE-A11), a coactivator that increases AR transcriptional activity during prostate cancer progression to castration-resistant/recurrent prostate cancer (CRPC).

Methods: Microarray analysis and quantitative RT-PCR were performed to identify androgen-regulated MAGE-A11-dependent genes in LAPC-4 prostate cancer cells after lentivirus shRNA knockdown of MAGE-A11.

Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells.

Genistein is a soy isoflavone with phytoestrogen and tyrosine kinase inhibitory properties. High intake of soy/genistein has been associated with reduced breast cancer risk. Despite the advances in genistein-mediated antitumor studies, the underlying mechanisms remain unclear.

Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK.

Although alcohol is an established breast cancer risk factor, the underlying mechanisms remain unclear. Previous studies examined the general association between alcohol consumption and breast cancer risk; however, the risk for different breast cancer subtypes has been rarely reported. Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking hormone receptors and HER2 expression, and having poor prognosis.

p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells.

The p53 tumor repressor gene is commonly mutated in human cancers. The tumor inhibitory effect of metformin on p53-mutated breast cancer cells remains unclear. Data from the present study demonstrated that p53 knockdown or mutation has a negative effect on metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells.