Impact of mutant beta-catenin on ABCB1 expression and therapy response in colon cancer cells

Background: Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/beta-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function beta-catenin on the chemoresistant phenotype. Methods: The effect of mutant (mut) beta-catenin on ABCB1 expression and promoter activity was examined using HCT116 human colon cancer cells and isogenic sublines harbouring gain-of-function or wild-type beta-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening. Results: Cell lines with mut beta-catenin showed high ABCB1 promoter activity and expression. Transfection and siRNA studies demonstrated a dominant role for the mutant allele in activating ABCB1 expression. Patients' primary colon cancer tumours shown to express the same mut beta-catenin allele also expressed high ABCB1 levels. However, cell line chemosensitivities towards 24 MDR-related and non-related antitumour drugs did not differ despite different beta-catenin genotypes. Conclusion: Although ABCB1 is dominantly regulated by mut beta-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same beta-catenin mutation was detected. The functional significance of the mutation for predicting patients' therapy response or for individualisation of chemotherapy regimens remains to be established

Holding onto womanhood: a qualitative study of heterosexual women with sexual desire loss

This article explores heterosexual women’s accounts of sexual desire loss, particularly the ways in which it can affect their sense of themselves as women. In-depth interviews were conducted with 17 participants recruited through a psychosexual clinic in England, and the data analysed using a material-discursive approach. The findings showed that having sexual desire loss often challenged participants’ perceptions of themselves as women. Specific challenges related to dealing with isolation and ‘otherness’, addressing their own feelings of not being ‘proper wives’ because they did not sexually satisfy their partners and maintaining a sense of sexual attractiveness in the absence of sexual desire. Participants responded to these challenges in various ways, often renegotiating their identities as women. The findings are discussed in relation to theorizing women’s sexuality and their implications for health care