RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells

Abstract

Breast cancer stem cells (BCSC) are presumed to be responsible for treatment resistance, tumor recurrence and metastasis of breast tumors. However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. Here, we demonstrate that RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is expressed in a subset of BCSCs in vivo and its function is required for the maintenance of BCSCs and their chemoresistance to doxorubicin. In human breast cancer cell line MCF7, RAC1B is required for BCSC plasticity and chemoresistance to doxorubicin in vitro and for tumor-initiating abilities in vivo. Unlike Rac1, Rac1b function is dispensable for normal mammary gland development and mammary epithelial stem cell (MaSC) activity. In contrast, loss of Rac1b function in a mouse model of breast cancer hampers the BCSC activity and increases their chemosensitivity to doxorubicin treatment. Collectively, our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy.

RAC1b Collaborates with TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

“…The availability of those biomarkers may facilitate the selection of patients and the optimal time for treatment with regard to TGF-β activity. There is also evidence from other cancer types that RAC1b [29,30], TAp73 [31,32] and BGN [33][34][35] all promote chemoresistance and that they may even operate through the same downstream signaling, i.e., NF-κB [30,33]. Future studies should reveal if the levels or activation states of TAp73 and/or RAC1b in patients could aid in assessing whether the oncogenic-or tumor-suppressive actions of TGF-β predominate at a given time.…”

HER2 overexpression initiates breast tumorigenesis non-cell-autonomously by inducing oxidative stress in the tissue microenvironment

“…In MMTV-NIC mouse line, all nulliparous females develop mammary tumors at around 4-5 months of age 16,18 . Although all five pairs of their mammary glands are prone to develop tumors, palpable tumors often develop quicker in their thoracic and cervical glands compared with their inguinal glands.…”

“…Primary cells from murine mammary tumors or murine mammary glands were isolated using the protocol described previously 18 . Mammosphere formation assay was performed as previously described in detail elsewhere 18,49 .…”

“…Primary cells sorted by FACS were cytospun on microscope slides and stained with antibodies as previously described 18 . Primary antibodies used were Anti-Cytokeratin-14 (PA5-16722, Invitrogen) and Anti-Cytokeratin-18 (61028, Progen); with secondary antibodies Donkey Anti-Rabbit AlexaFluor 488 (#A21206, Invitrogen) and Donkey Anti-Mouse AlexaFluor 594 (#A21203, Invitrogen).…”