A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers

Abstract

AbstrAct:Specific changes in gene expression during cancer initiation should enable discovery of biomarkers for risk assessment, early detection and targets for chemoprevention. It has been previously demonstrated that altered mRNA and proteome signatures of morphologically normal cells bearing a single inherited "hit" in a tumor suppressor gene parallel many changes observed in the corresponding sporadic cancer. Here, we report on the global gene expression profile of morphologically normal, cultured primary breast epithelial and stromal cells from Li-Fraumeni syndrome (LFS) TP53 mutation carriers. Our analyses identified multiple changes in gene expression in both morphologically normal breast epithelial and stromal cells associated with TP53 haploinsufficiency, as well as interlocking pathways. Notably, a dysregulated p53 signaling pathway was readily detectable. Pharmacological intervention with the p53 rescue compounds CP-31398 and PRIMA-1 provided further evidence in support of the central role of p53 in affecting these changes in LFS cells and treatment for this cancer. Because loss of signaling mediated by TP53 is associated with the development and survival of many human tumors, identification of gene expression profiles in morphologically normal cells that carry "one-hit" p53 mutations may reveal novel biomarkers, enabling the discovery of potential targets for chemoprevention of sporadic tumors as well.

Prostaglandin E2 down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity–breast cancer connection

“…An immortalized human mammary ASC line (HMS32-hTERT) was provided by Dr. Brittney-Shea Herbert (Indiana University School of Medicine) and grown as described previously (28,(41)(42)(43). Primary human breast ASCs and media were purchased from Zen-Bio.…”

Loss of p53 expression is accompanied by upregulation of beta‐catenin in meningiomas: a concomitant reciprocal expression

“…First indications came from reports that Wnt signalling is activated in cells derived from Li–Fraumeni syndrome patients who carry germ‐line monoallelic TP53 mutations (Herbert et al . ; Okayama et al . ).…”

“…There are several reports on the crosstalk of Wnt and p53 signalling pathways (Sadot et al 2001;Levina et al 2004;Kim et al 2011;Okayama et al 2014). First indications came from reports that Wnt signalling is activated in cells derived from Li-Fraumeni syndrome patients who carry germ-line monoallelic TP53 mutations (Herbert et al 2010;Okayama et al 2014). It has been shown that the excess p53 reduces beta-catenin protein levels and p53 can restrain Wnt signalling (Sadot et al 2001;Levina et al 2004;Kim et al 2011).…”

Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the plant natural product berberine

“…Over the past 35 years, many genes have been identified which can cause or contribute to the formation of cancer. 27,28 These include two major classes of genes, the oncogenes [29][30][31][32][33] and the tumor-suppressor genes such as retinoblastoma (RB), [34][35][36][37] TP53, [38][39][40] BRCA1, 41,42 PTEN, 43 TSC1 and TSC2. [44][45][46][47] Many of these oncogenes and tumor suppressors are often critical regulators of cellular senescence.…”