HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics

Frequent residential mobility among American Indians and early indications of sexual risk among young adolescents.

American Indian and Alaska Native (AI/AN) youth are more likely to ever have had sex, and to have engaged in sexual activity prior to age 13 compared to all other race groups. It is essential to understand the development of skills to refuse sexual experience in early adolescence in order to reduce disparities associated with early sexual debut among AI/AN youth. Familial, social, and individual factors can act as protective influences on adolescent sexual experience; however, in other settings, research has shown that frequent residential mobility disrupts these protective influences and may increase the likelihood of adolescent sexual activity. AI/AN youth are highly mobile, and, as a result, may be especially vulnerable to increased sexual risk. To date, no prior study has considered the impact of residential mobility on AI/AN youth sexual experience, nor the influence on precursors that reduce initiation of sex. We used data from a longitudinal study of AI/AN youth attending all middle schools from a Northern Plains reservation from 2006-2009 to estimate a structural equation model based on a cultural and age adapted theoretical framework. The tested model included frequent residential mobility as the independent variable and sex refusal self-efficacy as the dependent variable. Mediating variables included factors related to individual risks, psychological well-being, and social supports. Results indicate a direct association between residential mobility and sex refusal self-efficacy (-.29, p = 0.05) and an indirect association mediated by deviant peers (-.08, p = .05). Other mediating variables did not provide insight on the mechanism by which residential mobility influences skills to refuse sexual intercourse among AI/AN youth in early adolescence. Findings provide evidence for an association between residential mobility and precursors to sexual experience suggesting augmenting sexual health interventions for highly mobile youth

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics

Marijuana Initiation in 2 American Indian Reservation Communities: Comparison With a National Sample

Objectives. We examined disparities in age-related patterns of marijuana initiation in 2 culturally distinct American Indian reservation communities (from the Northern Plains and the Southwest) compared with a national sample