Abstract 2091: Atypical relationship between cytochrome P450 1B1 (CYP1B1) polymorphism and cell proliferation and invasiveness in head-and-neck carcinoma
Authors: Le Morvan Valérie , Richard Elodie , Cadars Maud , Pasquies Alban , Lansiaux Amélie , Robert Jacques 
Published: July 2016

We have previously shown a close association between a single nucleotide polymorphism (SNP) of cytochrome P450 1B1 (CYP1B1) (V432L, rs1056836) and in vitro sensitivity to several anticancer agents. From squamous cell carcinoma (HNSCC) cell lines not expressing this cytochrome, CAL27 and CAL33, we generated by lentiviral infection isogenic derivatives expressing to similar levels the two variant forms of CYP1B1.

Cell lines re-expressing CYP1B1 had higher proliferation and invasiveness than the original ones, and this was further increased when they expressed the variant form, which were significantly resistant to cisplatin and camptothecin. This was confirmed by in vivo studies in SCID mice: tumors re-expressing CYP1B1 had growth acceleration, especially those expressing the variant form. Treatment by cisplatin, irinotecan and doxorubicin induced regression of tumors obtained from vector-only infected cells, while those obtained from cells re-expressing CYP1B1, especially the variant form, were markedly resistant to all three drugs.

Four proteins representative of epithelial and mesenchymal phenotypes were determined by western blots. In the CAL33 cell line, the expression of E-cadherin and claudin-1 (epithelial markers) was decreased upon re-expression of CYP1B1, whereas the expression of N-cadherin and vimentin (mesenchymal markers) was increased. In the CAL27 cell line, this was the same only for mesenchymal markers. Using the Aldefluor assay kit, a stem cell phenotype was exhibited by the CAL27 line re-expressing the CYP1B1 variant genotype.

In silico studies on the collections of cancer cell lines (NCI-60 and CCLE) confirmed the significant association between CYP1B1 polymorphic status and resistance to DNA-damaging drugs. In addition, the variant genotype was associated to a mesenchymal phenotype defined by significant overexpression of series of 8-12 genes including vimentin and moesin, whereas the common and heterozygous genotypes were associated to an epithelial phenotype defined by significant overexpression of a series of 20-30 genes, including claudins 3, 4 and 7, E-cadherin and EPCAM.

The clinical consequences of the CYP1B1 L432V gene polymorphism were studied in a prospective population of 125 head-and-neck cancer patients (pts) treated in the palliative setting: 48 pts with common homozygous genotype (CH), 40 heterozygotes (HT) and 35 variant homozygous pts (VH). No differences in response rates as a function of the polymorphism were noticed. Overall median survival was significantly worse in VH pts (6.6 months) than in CH (13.2 months), HT falling in between (9.8 months) (p = 0.017).

As a conclusion, CYP1B1 appears to be involved in cell proliferation and invasiveness, these properties being magnified when expressed under its homozygous variant form, which is suggested to be associated to the epithelial-to-mesenchymal transition.

Citation Format: Valérie Le Morvan, Elodie Richard, Maud Cadars, Alban Pasquies, Amélie Lansiaux, Jacques Robert. Atypical relationship between cytochrome P450 1B1 (CYP1B1) polymorphism and cell proliferation and invasiveness in head-and-neck carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2091.