The molecular heterogeneity of the precancerous breast affects drug efficacy.

Autor: Bhardwaj A; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. abhardwaj@mdanderson.org., Rojo RD; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; College of Medicine, University of the Philippines Manila, Quezon City, Philippines., Ju Z; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Koh A; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Tachibana K; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan., Wang J; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Bedrosian I; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ibedrosian@mdanderson.org.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Jul 22; Vol. 12 (1), pp. 12590. Date of Electronic Publication: 2022 Jul 22.
DOI: 10.1038/s41598-022-16779-y
Abstrakt: In the therapeutic domain, targeted therapies have been shown to be generally more effective when given to patients with tumors that harbor the targeted aberration. This principle has not been tested in cancer prevention despite evidence that molecular heterogeneity accompanies the multi-step progression to invasive disease. We hypothesized that efficacy of agents targeting the precancerous state varies based on timing of the treatment relative to the underlying molecular changes. MCF10A cell line-based model of the multi-step progression to TNBC was used. Global proteomic patterns were obtained and growth-inhibitory effects of selected agents were correlated with the underlying molecular stage of progression. These analyses revealed that most protein alterations were acquired in the normal-to-atypia (preneoplasia) transition, with only handful aberrations acquired hereafter. The efficacy of small molecule inhibitors of the AKT/MEK pathway was associated with the underlying pathway levels. Similarly, fluvastatin was more effective in inhibiting cell proliferation earlier in the progression model. However, the nonspecific inhibitors, aspirin and metformin, were equally ineffective in inhibiting proliferation across the progression model. Our data provides proof-of-principle that in the prevention domain, treatment with agents developed to target specific pathways, will need to consider the molecular heterogeneity of the precancerous breast in order to achieve maximum efficacy.
(© 2022. The Author(s).)
Databáze: MEDLINE
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