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Physical Intimacy of Breast Cancer Cells with Mesenchymal Stem Cells Elicits Trastuzumab Resistance through Src Activation.

ABSTRACT: The development of resistance to trastuzumab is a major obstacle for lasting effective treatment of patients with ErbB2-overexpressing tumors. Here, we demonstrate that the physical contact of breast cancer cells with mesenchymal stem cells (MSCs) is a potential modulator of trastuzumab response by activation of nonreceptor tyrosine kinase c-Src and down regulation of phosphatase and tensin homolog (PTEN). Using an in vitro patterned breast cancer/MSC co-culture model, we find that the presence of MSCs results in Src activation that is missing in cancer cells monoculture, transwell co-culture, and cells treated with MSCs conditioned media. Interestingly, the co-culture model also results in PTEN loss and activation of PI3K/AKT pathway that has been demonstrated as fundamental proliferative and survival pathways in clinical settings. To our knowledge, this is the first report that showed PTEN loss without the use of chemical inhibitors, matrix stiffness, or silencing RNAs. In addition, breast cancer cells in co-culture with MSCs conferred trastuzumab resistance in vitro as observed in the lack of inhibition of proliferative and migrative properties of the cancer cells. Our findings show that MSCs are potent mediators of resistance to trastuzumab and might reveal targets to enhance trastuzumab efficacy in patients.

SUBMITTER: Daverey A

PROVIDER: S-EPMC4561910 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: COVID-19 has had a profound impact on relationship functioning, though effects have been heterogeneous. Reasons for divergent effects on relationship functioning remain unclear. Theoretical models suggest that it is not just stress exposure that leads to adverse relationships outcomes, but also subjective response to these stressors. Using data from a 14-day intensive longitudinal study of romantic dyads, we hypothesized that COVID-19-related distress would adversely impact one’s own and one’s partner’s report of relationship functioning, on average. Interdependence at the trait level (random effects between couples) and day level (residuals within couples) was also examined. Methods: Participants were 104 female-male romantic couples cohabiting the New York metropolitan area (Mage = 28.86, SDage = 7.69) between August 2020 – April 2021. Couples reported COVID-19 distress during a baseline interview and daily relationship functioning for 14 days. Multilevel models were specified for six outcomes simultaneously: female and male partner daily physical intimacy, emotional intimacy, and loneliness. Interrelationships of the intercepts of the six outcomes were specified, reflecting trait-level associations of each partner’s stable outcome tendencies. Interrelationships of the daily residuals of the six outcomes were also specified, reflecting within-couple associations at the daily level. Results: Female partner COVID-19 distress was inversely associated with her own emotional and physical intimacy and positively associated with her own and her partner’s loneliness. Male COVID-19 distress was associated with his own loneliness only. There was significant interdependence at both levels, such that greater loneliness in either partner was associated with less intimacy in each member of the couple. Discussion: Only one partner effect for COVID-19 distress emerged, such that female partner distress was associated with male partner loneliness; however, trait- and day-level interdependence suggested that distress may adversely impact relational well-being over time. Future studies should examine reciprocal relationships between COVID-19-related distress and relationship functioning.

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Physical Intimacy of Breast Cancer Cells with Mesenchymal Stem Cells Elicits Trastuzumab Resistance through Src Activation.

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