Preventing breast cancer will require the development of targeted strategies that can effectively block disease progression. Tamoxifen and aromatase inhibitors are effective in addressing estrogen receptor–positive (ER⁺) breast cancer development, but estrogen receptor–negative (ER⁻) breast cancer remains an unmet challenge due to gaps in pathobiologic understanding. In this study, we used reverse-phase protein array to identify activation of Src kinase as an early signaling alteration in premalignant breast lesions of women who did not respond to tamoxifen, a widely used ER antagonist for hormonal therapy of breast cancer. Src kinase blockade with the small-molecule inhibitor saracatinib prevented the disorganized three-dimensional growth of ER⁻ mammary epithelial cells in vitro and delayed the development of premalignant lesions and tumors in vivo in mouse models developing HER2⁺ and ER⁻ mammary tumors, extending tumor-free and overall survival. Mechanistic investigations revealed that Src blockade reduced glucose metabolism as a result of an inhibition in ERK1/2–MNK1–eIF4E–mediated cap-dependent translation of c-Myc and transcription of the glucose transporter GLUT1, thereby limiting energy available for cell growth. Taken together, our results provide a sound rationale to target Src pathways in premalignant breast lesions to limit the development of breast cancers. Cancer Res; 75(22); 4863–75. ©2015 AACR.

Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies – “redlining,” zoning, and the construction of highways – which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM_2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer.

During puberty, a woman’s breasts are vulnerable to environmental damage (“window of vulnerability”). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.