Harnessing protein kinase A activation to induce mesenchymal-epithelial programs to eliminate chemoresistant, tumor-initiating breast cancer cells

Alex J. Gooding, William P. Schiemann


Metastatic dissemination of primary tumors remains the most significant predictor of clinical outcomes of cancer patients, as well as the most lethal characteristic of human malignancies, including those that arise in the breast (1,2). Breast tumors are highly heterogeneous and comprised of numerous subclones that emanate from an array of genetic and epigenetic variants that coalesce in enhancing the fitness of disseminated cells upon their colonization of distant vital organs (3). Moreover, disseminated tumor cells (DTCs) are typically the culprits underlying clinical relapse in breast cancer patients, a process that transpires through the ability of DTCs to acquire tumor-initiating/stem-like and chemoresistant phenotypes, traits that cement DTCs as one of the foremost barriers to eradicating metastatic disease. The molecular mechanisms responsible for metastatic relapse and chemoresistance are multipartite and remain to be fully elucidated; however, recent findings implicate epithelial-mesenchymal transition (EMT) programs as a major driver that (I) induces metastatic cells to detach and egress from the primary tumor; and (II) enables DTCs to surmount the cellular and genotoxic stressors imposed by foreign microenvironments and cytotoxic therapies (4-7). In the most general sense, EMT programs reflect an organized transdifferentiation process whereby polarized epithelial cells shed their immotile behaviors in favor of newly acquired fibroblastoid-like phenotypes characterized by increased invasive and migratory capabilities that compel indolent carcinoma in situ lesions to become highly aggressive invasive lesions (4,7-9).