title: HER2 drives Mucin-like 1 to control proliferation in breast cancer cells.
abstract: Mucin-like 1 (MUCL1) was first identified as a breast-specific gene over a decade ago. Based on its highly restricted mRNA expression in breast tissue and continued expression during breast tumorigenesis and progression, MUCL1 is an attractive tumor-associated antigen and a potential therapeutic target. However, very little is known about the cellular location, biological functions and regulation of the MUCL1 protein, which will have a major impact on its druggability. Here we describe our efforts to fully characterize the cellular localization of MUCL1, investigate its regulation by key breast cancer oncogenes such as human epidermal growth factor receptor 2 (HER2) and discover its functional roles in breast cancer. Although some mucins are membrane bound, our data indicate that MUCL1 is secreted by some breast cancer cells, whereas others only express high levels of intracellular MUCL1. MUCL1 expression is highest in HER2-amplified breast tumors and inhibiting HER2 activity in tumor cells resulted in a decreased MUCL1 expression. In-depth investigation demonstrated that phosphoinositide3-kinase/Akt pathway, but not Ras/MEK pathway, controls MUCL1 expression downstream of HER2. Phenotypic assays revealed a strong dependence of HER2-positive cells on MUCL1 for cell proliferation. We further identified the mechanism by which MUCL1 regulates cell growth. Knockdown of MUCL1 induced a G1/S phase arrest concomitant with decreased cyclin D and increased p21 and p27 levels. Finally, we investigated the impact of MUCL1 loss on kinase signaling pathways in breast cancer cells through phospho-kinase array profiling. MUCL1 silencing abrogated phospho-focal adhesion kinase (FAK), Jun NH2-terminal kinase (JNK) and c-Jun signals, but not extracellular signal-regulated kinase or Akt pathway activities, thereby pointing to FAK/JNK pathway as the downstream effector of MUCL1 signaling. We are the first to identify an important role for MUCL1 in the proliferation of breast cancer cells, probably mediated via the FAK/JNK signaling pathway. Taken together, these data suggest a potential utility for therapeutic targeting of this protein in breast cancer.
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Conley
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Bosco
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Tice
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Hollingsworth
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Oncology Research, MedImmune, LLC, Gaithersburg, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D009077:Mucins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D009077:Mucins; D018719:Erb-b2 Receptor Tyrosine Kinases; C511061:MUCL1 protein, human; C508053:ERBB2 protein, human