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[Image: see text] The molecular determinants for the activities of the reported benzoic acid (SH4–54), salicylic acid (BP-1–102), and benzohydroxamic acid (SH5–07)-based STAT3 inhibitors were investigated to design optimized analogues. All three leads are based on an N-methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities and the CH(2) group of the glycinamide scaffold were separately modified. The replacement of the pentafluorobenzene or cyclohexylbenzene, or replacing the benzene ring of the aromatic carboxylic or hydroxamic acid motif with heterocyclic components (containing nitrogen and oxygen elements) all decreased potency. Notably, the Ala-linker analogues, 1a and 2v, and the Pro-based derivative 5d, all with (R)-configuration at the chiral center, had improved inhibitory activity and selectivity against STAT3 DNA-binding activity in vitro, with IC(50) of 3.0 ± 0.9, 1.80 ± 0.94, and 2.4 ± 0.2 μM, respectively. Compounds 1a, 2v, 5d, and other analogues inhibited constitutive STAT3 phosphorylation and activation in human breast cancer and melanoma lines, and blocked tumor cell viability, growth, colony formation, and migration in vitro. Pro-based analogue, 5h, with a relatively polar tetrahydropyranyl (THP) ring, instead of the cyclohexyl, showed improved permeability. In general, the (R)-configuration Pro-based analogs showed the overall best profile, including physicochemical properties (e.g., microsomal metabolic stability, Caco-2 permeability), and in particular, 5d showed improved tumor-cell specificity.

Exposures to carcinogens in hair products have been explored as breast cancer risk factors, yielding equivocal findings. We examined hair product use (hair dyes, chemical relaxers and cholesterol or placenta-containing conditioners) among African American (AA) and White women, and explored associations with breast cancer. Multivariable-adjusted models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to describe the associations of interest among 2280 cases (1508 AA and 772 White) and 2005 controls (1290 AA and 715 White). Among controls, hair dye use was more common among Whites than AAs (58 versus 30%), while relaxer (88 versus 5%) and deep conditioner use (59 versus 6%) was more common among AAs. Among AAs, use of dark hair dye shades was associated with increased breast cancer risk (OR = 1.51, 95% CI: 1.20-1.90) and use of dark shades (OR = 1.72, 95% CI: 1.30-2.26) and higher frequency of use (OR = 1.36, 95% CI: 1.01-1.84) were associated with ER+ disease. Among Whites, relaxer use (OR = 1.74, 95% CI: 1.11-2.74) and dual use of relaxers and hair dyes (OR = 2.40, 95% CI: 1.35-4.27) was associated with breast cancer; use of dark hair dyes was associated with increased ER+ disease (OR = 1.54, 95% CI: 1.01-2.33), and relaxer use was associated with increased ER- disease (OR = 2.56, 95% CI: 1.06-6.16). These novel findings provide support a relationship between the use of some hair products and breast cancer. Further examinations of hair products as important exposures contributing to breast cancer carcinogenesis are necessary.

Receptor tyrosine kinases-based autocrine loops largely contribute to activate the MAPK and PI3K/AKT pathways in melanoma. However, the molecular mechanisms involved in generating these autocrine loops are still largely unknown. In the present study, we examine the role of the transcription factor RUNX2 in the regulation of receptor tyrosine kinase (RTK) expression in melanoma. We have demonstrated that RUNX2-deficient melanoma cells display a significant decrease in three receptor tyrosine kinases, EGFR, IGF-1R and PDGFRβ. In addition, we found co-expression of RUNX2 and another RTK, AXL, in both melanoma cells and melanoma patient samples. We observed a decrease in phosphoAKT2 (S474) and phosphoAKT (T308) levels when RUNX2 knock down resulted in significant RTK down regulation. Finally, we showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL in melanoma cells resistant to the BRAF V600E inhibitor PLX4720. Taken together, our results strongly suggest that RUNX2 might be a key player in RTK-based autocrine loops and a mediator of resistance to BRAF V600E inhibitors involving RTK up regulation in melanoma.

Introduction: Over the last several decades, the concern of environmental exposures to certain carcinogens and mutagens found in hair products, particularly hair dyes, have been explored for evidence of an association with breast cancer risk, yielding equivocal results. However, little is known about this association among African American (AA) women, who are common users of these products. The objective of this study was to examine the prevalence and patterns of use of hair products in AA and European American (EA) women in the Women's Circle of Health Study (WCHS), and their associations with breast cancer risk, overall and by estrogen receptor (ER+, ER-) and triple negative (TN) status. Methods: Data collection for the WCHS, a case-control study of breast cancer in New York City and several counties in New Jersey, was conducted through in-person interviews, with anthropometric and body composition measurements taken, and review of pathology records. At study entry, participants were asked on use of hair dyes, chemical relaxers/straighteners and cholesterol- and/or placenta-containing conditioning creams. Chi-square tests were used to compare differences in hair product variables by case-control status among AAs and EAs. Race-stratified, age-adjusted and multivariable-adjusted unconditional logistic regression models controlling for age, race, education, family history of breast cancer, oral contraceptive use, and body mass index were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between hair product use and risk among 4,285 women with breast cancer and controls (AA, n=2,798 and EA, n=1,487). Results: Among controls, 30.23% of AAs and 57.76% of EAs regularly used hair dye. Compared to light hair dye shades (blonde, light brown) use of darker shades (dark brown, black) was associated with increased odds of breast cancer among AA women (OR 1.64, 95% CI: 1.19-2.27), although there did not appear to be a dose response association with frequency of use. There were no associations between hair dye use and breast cancer risk among EA women. Use of chemical relaxers was more common among AAs than EAs (87.13% vs. 4.62% of AA and EA controls, respectively). Compared to AA women who used chemical relaxers without lye, those using products with lye were at increased risk (OR 1.54, 95% CI: 1.22-1.94). Among EA women although use of relaxers was not very common, compared to never users, those using relaxers (OR 1.74, 95% CI: 1.11-2.74) and using lye-containing relaxers (OR 4.37, 95% CI: 1.65-11.88) were at increased risk. Regular hair dye use (OR 1.20, 95% CI: 1.03-1.39), use of darker hair dye shades (OR 1.37, 95% CI: 1.05-1.77), and use of relaxers that contain lye (OR 1.26, 95% CI: 1.03-1.55) were associated with increased risk of ER+ BC. Regularly using both hair dyes and relaxers was associated with increased risk of ER+ BC (OR 1.20, 95% CI: 1.00-1.44). Regular hair dye use was not associated with risk of ER- or TNBC. The use of deep conditioning creams that contain cholesterol or placenta was also more common among AAs than EAs (56.12% vs. 6.01% of controls, respectively). However, there were no associations between use of these products and breast cancer risk. Conclusions: These findings from a large case-control study of AA and EA women provide additional epidemiological data to support a relationship between the use of some hair products, namely hair dyes and chemical relaxers, and risk of breast cancer. As use of various hair products and other cosmetics continue to increase among women in the U.S., particularly those at increased risk of breast cancer, improved awareness of the potential effects of exposures to their chemical ingredients are needed. Citation Format: Adana A.M. Llanos, Anna Rabkin, Gary Zirpoli, Cathleen Y. Xing, Bo Qin, Brian D. Gonzalez, Chi-Chen Hong, Kitaw Demissie, Elisa V. Bandera, Christine B. Ambrosone. Hair product use and breast cancer risk by hormone receptor status in the Women's Circle of Health Study. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B81.