br Introduction a broad range
1. Introduction a broad range of nuclear receptors including estrogen receptor alpha (ERα), a major driver of breast cancer development [1–4]. Although all Steroid receptor coactivators (SRCs) are a three-member family members of the SRC family may be implicated in similar cellular and (SRC-1, SRC-2 and SRC-3) of coactivators governing the transcription of physiological processes, recent advances in the field indicate that each
Abbreviations: CA, correspondence analysis; CDH, cadherin; cDNA, coding DNA; E2, 17β-estradiol; ECM, extracellular matrix; EMT, epithelial to mesenchymal transition; ERα, estrogen receptor alpha; FBS, fetal bovine serum; FC, flow cytometry; FDR, false discovery rate; GO, gene ontology; HE, hematoxylin and eosin; Lyn, v-yes-1 Yamaguchi sarcoma viral related oncogene homolog; MCM7, minichromosome maintenance complex component 7; MET, mesenchymal to epithelial tran-sition; Myb, myeloblastosis viral oncogene homolog; NSC, non-specific siRNA control; PGR, progesterone receptor; PUM1, pumilio RNA-binding family member 1; RPLP0, ribosomal protein, large, P0; RT-qPCR, quantitative real-time PCR; SAM, significance analysis of microarray; shRNA, short hairpin RNA; siRNA, small interfering RNA; SNAI, snail family zinc finger; TBP, TATA box binding protein; TNBRCA, triple-negative breast cancer
Corresponding author at: Hormone Laboratory, Haukeland University Hospital, N-5021, Bergen, Norway.
E-mail addresses: [email protected] (O. Bozickovic), [email protected] (L. Skartveit), [email protected] (A.S.T. Engelsen),
[email protected] (T. Helland), [email protected] (K. Jonsdottir), [email protected] (M.H. Flågeng), [email protected] (I.S. Fenne), [email protected] (E. Janssen), [email protected] (J.B. Lorens), [email protected] (L. Bjørkhaug), [email protected] (J.V. Sagen), [email protected] (G. Mellgren). 1 Both authors equally contributed to this work.
O. Bozickovic et al.
of the SRCs may occupy a unique niche of biological activity. SRC-2 and SRC-3 are involved in both normal development and malignant trans-formation of the breast tissue. Specifically, knock-out studies in mice have shown that SRC-2 is involved in mammary gland branching during puberty, SRC-3 is involved in the growth of the mammary gland ducts, while both SRC-2 and SRC-3 promote alveolar development in breast tissue [5,6]. SRC-3 overexpression elevates the number of epithelial Puromycin and increases mammary gland size and disorganization, denoting the onset of ductal carcinoma in situ, an early non-invasive stage of breast cancer . Reduced expression of SRC-3 and its cytoplasmic localization correlate with the increased diﬀerentiation of the mam-mary gland .
The specific transcriptional role of SRC-2 in breast cancer is still unclear. Tumorigenic changes induced by SRC-2 have been attributed mostly to its role in transcriptional regulation of cell proliferation [4,9]. SRC-2 has also been described as an estrogen-independent activator of cell proliferation . Due to its mixed transcriptional function, SRC-2 cannot be classified as a true oncogene and presents a challenging subject for further investigation. Unlike SRC-2, SRC-3 is a well-estab-lished oncogene in breast cancer. Aside from its role in proliferation, SRC-3 has recently also been characterized as an inducer of epithelial-to-mesenchymal transition (EMT) during the metastatic process of in-vasive ductal carcinoma [11,12]. EMT is a crucial process in cancer-ogenesis where epithelial non-migratory cells re-diﬀerentiate into me-senchymal-like migration-prone cells. This leads to invasion of malignant breast cancer cells into secondary sites, which is character-istic of the later metastatic cancer stages. An important property of metastatic cells is their stemness, the proclivity of certain cancer cell subtypes to survive and develop into metastases in distal tissues, which contributes to a more aggressive breast cancer phenotype (reviewed in [13,14]). EMT and stemness are considered to be functionally con-nected via gene expression (reviewed in ). In order to define genes involved in both EMT and stemness in breast cancer, a comprehensive single-cell analysis was recently performed . The study linked a clinically established EMT gene profile to the stemness potential of individual metastatic cells, resulting in an EMT/stemness signature gene set in breast cancer and included the more aggressive subset of breast cancers, the basal, stem-like triple-negative breast cancer (TNBC). One possible target of interest in TNBC is Lyn, which is a proto-oncogenic Src-type kinase associated with the surface receptors such as B-cell receptor, GM-CSF-receptor, c-Kit and EGFR [17–20]. The ex-pression of Lyn is positively associated with shorter overall survival in breast cancer patients and the TNBC phenotype .