Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism.

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.

Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression.

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.

Is it contagious? Affect similarity among spouses.

Theories of emotional contagion suggest that spouses mutually experience affective or emotional states. However, empirical support for this theory is limited. Using a dyadic approach, this study examines affect similarity of depressive symptoms between elders with vision impairment and their spouses. As part of an investigation on older couples dealing with disability, 123 elders dealing with a recent vision loss and their spouses were interviewed. Guided by a stress process model, predictors of spouse depressive symptoms were examined. Hierarchical regression analyses revealed that the spouse's race, health, care-giving appraisal, self-efficacy, conflict with other family members regarding their partner, and their partner's depressive symptoms significantly predicted spouse depression. Specifically, spouses who were white, in poorer health, experienced more care-giving burden, had more family conflict, and poorer self-efficacy, were more likely to be depressed. Entered in the final step, elder depression uniquely contributed to the prediction of spouse depression. This points to affect similarity among spouses, which suggests that when one spouse is depressed, the other spouse is likely to experience a similar depressive symptomatology.

A randomized comparison study of drop versus spray topical cycloplegic application.

PURPOSE: To evaluate the acceptance of ocular spray administration. METHODS: A randomized, single-masked comparison in a cohort of children from 3 to 13 years. Assessment of patient pain was recorded on a visual analog scale. Cycloplegia was assessed by an ophthalmologist masked to the assignment. A questionnaire was used to assess patient acceptance. 126 patients participated. The average age was 7.7 years for spray, 7.1 for drops. RESULTS: Pain (higher number = more painful): means: 41/100 for spray; 35/100 for drops (P=0.28). No difference in cycloplegia noted (i.e., satisfactory in all subjects). Subjective acceptance: high in both patient groups, but a preference for spray was noted (P=0.06). No untoward drug reactions occurred with either method. CONCLUSIONS: Cycloplegic spray was as acceptable, or more acceptable than drops. Cycloplegia was comparable for the two methods. Spray application of cycloplegic drugs is a satisfactory route of topical administration for children.

Should early strabismus surgery be performed for ocular torticollis to prevent facial asymmetry?

To help determine whether ocular torticollis causes facial asymmetry, we analyzed photographs of patients with long-standing head tilts for amounts of tilt and facial asymmetry. Significant facial asymmetry that correlated with the side of the head tilt was found in patients with congenital superior oblique muscle paresis, but not in patients with traumatic superior oblique muscle paresis nor in patients with dissociated vertical deviation. The mechanism explaining the development of facial asymmetry in these patients may be deformational molding of the face and skull from the infant's sleeping with its head turned predominantly to one side during the first 6 to 12 months of life. Early strabismus surgery to correct the head tilt may help prevent facial asymmetry, but ensuring that the infant sleeps with alternating head positions may be more important.

Ecological measures of cognitive functioning: a validation study.

Observed cognitive decline in the elderly has been widely reported in the literature. The relation of experimental cognitive ability measures to real-world cognitive competence has been questioned. This research examines the validity of English-language versions of two measures of everyday competency: the Memory in Reality test involving object placement recall and the Coin Test, a money-sorting task. The measures were developed as part of a Swedish epidemiologic study. Validity was evaluated by comparison of these tasks with standard cognitive tests and with a measure of metamemory. It was expected that the ecological measures would have a stronger association with metamemory than the standard tests. Subjects were 93 community-dwelling women, aged 75 and older. The ecological tasks correlated positively with the standard tests, but there were inconsistent relations of both standard and ecological measures with metamemory. The results partly support use of these measures for evaluating everyday functioning.