A Distinct Epigenome of Invasive Lobular Breast Cancers Drives Resistance to Tamoxifen

Invasive lobular breast cancer (ILC) is the second most frequently diagnosed histologic subtype of invasive breast cancer (BC) (10-15% of all invasive breast cancers). The most common feature of ILC (65% of cases) is the loss of the cell adhesion protein e-cadherin (CDH1, gene) and high expression of estrogen receptor (ER). More recent studies have shown that ILC is enriched in FOXA1 mutations compared to invasive ductal cancers (DC). As for response to treatment, neoadjuvant clinical trials showed that patients with ILC are relatively resistant to chemotherapy. In addition,  patients with ILC the decrease in benefit from adjuvant tamoxifen treatment versus aromatase inhibitors in more pronounced compared to patients with IDC. Collectively, these observations suggest that the ER axis in ILC may be different compared to IDC.

To investigate the ER transcriptional program in ILC and IDC we comprehensively studied ILC and IDC cell line models. We first confirmed the clinical relevance of these models. By performing multi-omic analyses including ER/FOXA1/GATA3 /H3K27 ChIP-seq, and ATACseq we found that ILC has a unique ER cistrome that is dictated by differential recruitment of FOXA1. In addition, we show that ILC is epigentically different from IDC and these differences are also associated with a unique FOXA1 cistrome. In keeping with the clinical data, the ILC cells are resistant to tamoxifen but remain sensitive to estrogen deprivation and ER silencing.  In this work, we have identified one of the mechanisms by which ILCs are relatively resistant to tamoxifen. Lastly, we show that the reprogramming of the ER axis in ILC is not linked to CDH1 loss.

In summary, we provide novel insights to the biology of ILCs. We show that ILC has a unique ER transcriptional program driven by differences in the chromatin accessibility landscape and FOXA1 binding. These findings are independent of ECAD loss indicating that differences between IDC and ILC are far more complex than ECAD loss alone.

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