Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Abstract

Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct antiestrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

“…Both MMP9 and MMP3 have been reported to be important for breast tumorigenesis (Kessenbrock et al, 2013; Qin et al, 2008). In addition, the metastasis promoting periostin ( POSTN ) and the platelet-derived growth factor receptor ( PDGFRA ) genes that have been implicated in endocrine resistance were among the up regulated genes (Malanchi et al, 2012; van Agthoven et al, 2010). Both the MMP3 and POSTN genes are involved in Wnt/B-catenin signaling (Kessenbrock et al, 2013; Malanchi et al, 2012).…”

LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy

“…Therefore, it is of vital importance to identify the factors and mechanisms involved in tamoxifen resistance. Several studies have previously identified so-called BCAR (breast cancer anti-estrogen resistance) genes (van Agthoven et al 2010, Duan et al 2011. In this study, we have shown that LAMP3 is also a factor involved in anti-estrogen resistance.…”

Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers

“…The majority of patients included in this study still responded to treatment after three months, however, acquired resistance to endocrine treatment may develop as a consequence of a serial of complex adaptive changes occurring in breast cancer cells during the selective pressure of long-term endocrine treatment [40]. Notably, in vitro studies have linked both EGFR/HER-1 and NRG1 expression levels to endocrine resistance [41]. Thus, the possibility exists that induction of EGFR/HER-1 during antihormone therapy may affect proliferation over time, leaving cells more sensitive to mitogenic effects of growth factors [37].…”