Introduction: Little is known about the evolution of proteomic aberrations during TNBC tumorigenesis and whether the timing of intervention for prevention and treatment during this tumorigenic progression impacts efficacy. We hypothesized that the targeted therapies for TNBC is likely to be context specific, with specific transition points where such therapy is likely to be most effective based on presence of proteomic aberrations. Methods: MCF10A cell line-based model of triple negative breast cancer progression was used. This model system comprises of non-cancer MCF10A (P), preneoplastic MCF10.AT1 and MCF10.NeoT, premalignant ductal carcinoma in situ MCF10.DCIS and invasive MCF10.CA1D cells. Global proteomic patterns were studied by performing RPPA assay. Growth inhibitory effects drugs were studied by measuring inhibition in cell proliferation by MTT assay. Results: RPPA analysis revealed a majority of protein alterations (n=48) were acquired early on during TNBC progression, specifically during normal to preneoplastic (atypia) transition, with only 6 aberrations acquired in later stages of tumorigenesis. To assess the effects of this heterogeneity on efficacy of treatment, we selected 2 aberrant pathways that were up-regulated early in the breast tumorigenesis and compared efficacy of targeted intervention to drugs without pathway selectivity. Targeting upstream oncogenic pathways with small molecule inhibitors (AKT pathway with LY294002- a PI3 kinase inhibitor and MEK pathway with MEK1/2 inhibitors PD032590 or GSK1120212) showed PI3K inhibitor to be equally effective in suppressing the cell proliferation in both preneoplastic and DCIS state, consistent with upregulation of the underlying AKT pathway aberration early in tumorigenesis. MEK pathway inhibitors were preferentially more effective in preneoplastic state than DCIS state, consistent with continued activation of MEK pathway in the DCIS state relative to preneoplastic state. Similarly, fluvastatin (a cholesterol lowering drug) was more effective in inhibiting the cell proliferation in preneoplastic cells relative to DCIS cells. However, a broad spectrum drug aspirin (an AMPK activator) that is known to have pleotropic effects showed no differential effects across the cell lines tested. Conclusions: The preponderance of proteomic alterations occur in the very earliest stages of TNBC tumorigenesis. Effectiveness of targeted drug therapies in this model of breast tumorigenesis correlated. with deregulation of the associated pathway. This implies that accounting for heterogeneity of the preneoplastic breast and stage of tumorigenic progression will be important when considering targeted strategies for prevention.

Citation Format: Anjana Bhardwaj, Raniv Rojo, Zhenlin Ju, Jing Wang, Isabelle Bedrosian. Heterogeneity of preneoplastic breast tissues drives efficacy of therapeutic agents [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-11-10.